Mast cell stabilizers treatment for systemic disorders

ABSTRACT

Methods for the treatment of systemic disorders treatable with mast cell stabilizers, including mast cell related disorders, are provided.

CROSS-REFERENCE

This application is a National Stage Application, filed under 35 U.S.C.§ 371, of International Application No. PCT/US2015/015029, filed on Feb.9, 2015; which claims the priority benefit of U.S. ProvisionalApplication No. 61/937,928, filed Feb. 10, 2014; U.S. ProvisionalApplication No. 61/971,709, filed Mar. 28, 2014; U.S. ProvisionalApplication No. 61/978,711, filed Apr. 11, 2014; and U.S. ProvisionalApplication No. 62/105,423, filed Jan. 20, 2015, all of which areincorporated by reference herein in their entireties.

BACKGROUND OF THE INVENTION

Mast cells play a key role in the inflammatory process. They are foundin the perivascular spaces of most tissues and contain pro-inflammatoryand vasoactive mediators, such as serine proteases, tryptase, histamine,serotonin, proteoglycans, thromboxane, prostaglandin D2, leukotriene C4,platelet-activating factor, and eosinophil chemotactic factor. Whenactivated, mast cells rapidly release granules and various hormonemediators into the interstitium, a process referred to as degranulation.Degranulation of mast cells can be caused by physical or chemicalinjury, crosslinking of immunoglobulin G receptors, or by activatedcomplement proteins.

Systemic mast cell related disorders may result from excessiveproliferation of mast cells or abnormal release of pro-inflammatory andvasoactive mediators. Symptoms of systemic mast cell related disordersinclude pruritus, flushing, nausea, vomiting, diarrhea, headaches,abdominal pain, vascular instability, urticaria, itching, andanaphylaxis. Accumulation of mast cells in the skin, gastrointestinaltract, bone marrow, liver, spleen, and lymph nodes may result in aparticular systemic mast cell related disorder, systemic mastocytosis,or mastocytosis.

The utility of mast cell stabilizers in the treatment of systemic mastcell related disorders, such as mastocytosis, has been limited. Forexample, cromolyn sodium (also known as disodium cromoglycate or DSCG)was first approved in 1973 and is widely considered safe, but it hasfound limited utility because the amount of the compound that can bedelivered systemically is inadequate. An oral solution of cromolynsodium is available for the treatment of systemic mast cell relateddisorders, such as mastocytosis (Gastrocrom®). However, the oralsolution is only modestly effective for treating localizedgastrointestinal symptoms, and it is not effective for the treatment ofsystemic symptoms because of the low oral bioavailability of cromolynsodium (less than 1%).

Efforts have been made to increase the oral bioavailability of cromolynsodium in order to provide systemically effective amounts for thetreatment of systemic mast cell related disorders, but these effortshave not yielded products that achieve significantly higher oralbioavailability of cromolyn sodium in a practical, safe, andwell-tolerated manner. Accordingly, a need exists for methods ofdelivering mast cell stabilizers, such as cromolyn sodium, that achievehigher systemic levels than previously considered or thought possible,in a practical, safe, and well-tolerated manner, in order tosignificantly improve clinical outcomes for patients suffering fromsystemic mast cell related disorders.

SUMMARY OF THE INVENTION

The foregoing and further needs are satisfied by embodiments of themethods disclosed herein. Specifically, disclosed herein are methods oftreating a systemic mast cell related disorder by delivering asystemically effective amount of a mast cell stabilizer to a patient. Incertain embodiments, the systemic mast cell related disorder is selectedfrom the group consisting of a mast cell activation syndrome;mastocytosis; idiopathic urticaria; chronic urticaria; atopicdermatitis; idiopathic anaphylaxis; Ig-E and non Ig-E mediatedanaphylaxis; angioedema; allergic disorders; irritable bowel syndrome;mastocytic gastroenteritis; mastocytic colitis; fibromyalgia; kidneyfibrosis; atherosclerosis; myocardial ischemia; hypertension; congestiveheart failure; pruritus; chronic pruritus; pruritus secondary to chronickidney failure; heart, vascular, intestinal, brain, kidney, liver,pancreas, muscle, bone and skin conditions associated with mast cells;CNS diseases such as Parkinson's disease and Alzheimer's disease;metabolic diseases such as diabetes; sickle cell disease; autism;chronic fatigue syndrome; lupus; chronic lyme disease; interstitialcystitis; multiple sclerosis; cancer; migraine headaches; psoriasis;eosinophilic esophagitis; eosinophilic gastroenteritis; Churg-Strausssyndrome; hypereosinophilic syndrome; eosinophilic fasciitis;eosinophilic gastrointestinal disorders; chronic idiopathic urticaria;myocarditis; Hirschsprung's-associated enterocolitis; postoperativeileus; wound healing; stroke; transient ischemic attack; pain;neuralgia; peripheral neuropathy; acute coronary syndromes;pancreatitis; cutaneous mastocytosis; systemic mastocytosis; systemicindolent mastocytosis; dermatomyositis; fibrotic skin diseases; painassociated with cancer; ulcerative colitis; inflammatory bowel disease;radiation colitis; celiac disease; gluten enteropathy; radiationcystitis; painful bladder syndrome; hepatitis; hepatic fibrosis;cirrhosis; rheumatoid arthritis; lupus erythematosus; and vasculitis. Insome embodiments, administration of a composition disclosed herein in amethod disclosed herein is well-tolerated by the patient. In someembodiments, the mast cell stabilizer is selected from cromolyn sodium,cromolyn lysinate, ammonium cromoglycate, magnesium cromoglycate,dihydropyridines such as nicardipine and nifedipine, lodoxamide,nedocromil, barnidipine, YC-114, elgodipine, niguldipine, ketotifen,methylxanthines, and quercetin. In some embodiments, administration of acomposition disclosed herein in a method disclosed herein does not causeone or more adverse events selected from the group consisting oforopharyngeal pain, dysgeusia, nasopharygitis, and abdominal discomfort.

In some embodiments, the methods disclosed herein comprise administeringa composition comprising a mast cell stabilizer to a patient having asystemic mast cell related disorder, wherein the bioavailability of themast cell stabilizer is greater than about 5%, and whereinadministration of the composition produces in a human subject group anaverage AUC_((0-∞)) of the mast cell stabilizer greater than about 120ng*hr/mL and/or an average C_(max) of the mast cell stabilizer greaterthan about 55 ng/mL. In some embodiments of the methods disclosedherein, the composition is administered by a route selected frominhalation administration, oral administration, parenteraladministration, subcutaneous administration, topical administration,buccal administration, nasal administration, rectal administration,vaginal administration, and sublingual administration. In someembodiments, the composition is administered with a dry powder inhaler,metered dose inhaler, nebulizer, soft mist inhaler, or high efficiencynebulizer. In some embodiments wherein the composition is administeredwith a dry powder inhaler, the composition comprises lactose. In someembodiments wherein the composition is administered with a dry powderinhaler, the composition does not comprise lactose. In some embodiments,a composition comprising a mast cell stabilizer is administered once aday. In some embodiments, a composition comprising a mast cellstabilizer is administered twice a day. In some embodiments, acomposition comprising a mast cell stabilizer is administered threetimes a day. In some embodiments, a composition comprising a mast cellstabilizer is administered four times a day. In some embodiments, thecomposition comprises about 1 mg to about 120 mg of cromolyn sodium. Insome embodiments, the composition comprises about 5 mg to about 80 mg ofcromolyn sodium. In some embodiments, the composition comprises about 20mg to about 60 mg of cromolyn sodium. In some embodiments, thecomposition comprises about 30 mg to about 50 mg of cromolyn sodium. Insome embodiments, the composition comprises about 40 mg of cromolynsodium.

In some embodiments, disclosed herein is a method of treating a patienthaving a systemic mast cell related disorder comprising administering tothe patient a composition comprising a nominal dose of a mast cellstabilizer with a high efficiency nebulizer, wherein administration ofthe composition to the patient with a high efficiency nebulizer providesa systemically effective amount of the mast cell stabilizer to treat thesystemic mast cell related disorder. In certain embodiments, thebioavailability of the mast cell stabilizer is greater than about 5% ofthe nominal dose administered with the high efficiency nebulizer. Incertain embodiments, administration of the composition comprising a mastcell stabilizer with a high efficiency nebulizer produces in a humansubject group an average AUC_((0-∞)) of the mast cell stabilizer greaterthan about 120 ng*hr/mL and/or an average C_(max) of the mast cellstabilizer greater than about 55 ng/mL. In certain embodiments,administration of the composition comprising a mast cell stabilizer witha high efficiency nebulizer produces in a human subject group an averageAUC_((0-∞)) of the mast cell stabilizer greater than about 120 ng*hr/mLand an average C_(max) of the mast cell stabilizer greater than about 55ng/mL. In certain embodiments, the composition comprising a mast cellstabilizer comprises a high concentration, hypotonic, room temperaturestable solution formulation of the mast cell stabilizer. In certainembodiments, the composition is stable at room temperature for more thanabout two years. In some embodiments, the composition comprises one ormore of purified water, sodium chloride, mannitol, and sodium EDTA. Insome embodiments, the composition has an osmolality greater than about70 mOsm/kg. In some embodiments, the composition has a fill volume ofabout 0.1 mL to about 5 mL. In some embodiments, the composition has afill volume of about 2 mL or less. In some embodiments, the compositionis administered in less than about five minutes. In some embodiments,the composition is administered in less than about three minutes. Insome embodiments, the high efficiency nebulizer emits droplets having anMMAD of about 4.1 μm or less and a GSD of about 1.7. In someembodiments, the high efficiency nebulizer emits droplets having an MMADof about 3.5 μm or less and a GSD of about 1.7. In some embodiments, theRF (≤3.3 μm) is at least about 30% and/or the RF (≤5 μm) is at leastabout 65%. In some embodiments, the RF (≤3.3 μm) is at least about 45%and/or the RF (≤5 μm) is at least about 75%.

In some embodiments, the mast cell stabilizer is cromolyn sodium. Insome embodiments, the deposited lung dose of cromolyn sodium is at leastabout 25% after administration of the composition to the patient with ahigh efficiency nebulizer. In some embodiments, administration of thecomposition with a high efficiency nebulizer produces in a human subjectgroup an average AUC_((0-∞)) of the cromolyn sodium greater than about120 ng*hr/mL, an average C_(max) of the cromolyn sodium greater thanabout 55 ng/mL, and a deposited lung dose of cromolyn sodium at leastabout 25%. In some embodiments, the composition comprises greater thanabout 2% cromolyn sodium. In some embodiments, the composition comprisesabout 4% cromolyn sodium. In some embodiments, the median particle sizeof the cromolyn sodium aerosol is between about 3 μm and about 4 μm.

In certain embodiments of the methods disclosed herein, a compositioncomprising a mast cell stabilizer is administered with an inhalationdevice, wherein administration of the composition with the inhalationdevice produces in a human subject group an average AUC_((0-∞)) of themast cell stabilizer greater than about 120 ng*hr/mL and/or an averageC_(max) of the mast cell stabilizer greater than about 55 ng/mL. In someembodiments the mast cell stabilizer is cromolyn sodium, andadministration of the composition with an inhalation device produces ina human subject group an average AUC_((0-∞)) of the cromolyn sodiumgreater than about 120 ng*hr/mL and an average C_(max) of the cromolynsodium greater than about 55 ng/mL. In some embodiments the mast cellstabilizer is cromolyn sodium, and administration of the compositionwith an inhalation device produces in a human subject group an averageAUC_((0-∞)) of the cromolyn sodium greater than about 200 ng*hr/mL andan average C_(max) of the cromolyn sodium greater than about 80 ng/mL.In some embodiments the mast cell stabilizer is cromolyn sodium, andadministration of the composition with an inhalation device produces ina human subject group an average AUC_((0-∞)) of the cromolyn sodiumgreater than about 330 ng*hr/mL and an average C_(max) of the cromolynsodium greater than about 150 ng/mL. In some embodiments the mast cellstabilizer is cromolyn sodium, and administration of the compositionwith an inhalation device produces in a human subject group an averageAUC_((0-∞)) of the cromolyn sodium greater than about 525 ng*hr/mL andan average C_(max) of the cromolyn sodium greater than about 230 ng/mL.In some embodiments wherein the mast cell stabilizer is cromolyn sodiumand a nominal dose of 40 mg of cromolyn sodium is administered with theinhalation device, administration of the composition with the inhalationdevice produces in a human subject group an average AUC_((0-∞)) of thecromolyn sodium greater than about 200 ng*hr/mL and an average C_(max)of the cromolyn sodium greater than about 80 ng/mL. In some embodimentswherein the mast cell stabilizer is cromolyn sodium and a nominal doseof 40 mg of cromolyn sodium is administered with the inhalation device,administration of the composition with the inhalation device produces ina human subject group an average AUC_((0-∞)) of the cromolyn sodiumgreater than about 330 ng*hr/mL and an average C_(max) of the cromolynsodium greater than about 150 ng/mL. In some embodiments wherein themast cell stabilizer is cromolyn sodium and a nominal dose of 80 mg ofcromolyn sodium is administered with the inhalation device,administration of the composition with the inhalation device produces ina human subject group an average AUC_((0-∞)) of the cromolyn sodiumgreater than about 525 ng*hr/mL and an average C_(max) of the cromolynsodium greater than about 230 ng/mL. In some embodiments wherein themast cell stabilizer is cromolyn sodium, administration of a compositionwith an inhalation device provides a bioavailability of the mast cellstabilizer greater than about 5% and produces in a human subject groupan average AUC_((0-∞)) of cromolyn sodium greater than about 120ng*hr/mL. In some embodiments wherein the mast cell stabilizer iscromolyn sodium, administration of a composition with an inhalationdevice provides a bioavailability of cromolyn sodium greater than about5% and produces in a human subject group an average AUC_((0-∞)) ofcromolyn sodium greater than about 200 ng*hr/mL. In some embodimentswherein the mast cell stabilizer is cromolyn sodium, administration of acomposition with an inhalation device provides a bioavailability of themast cell stabilizer greater than about 5% and produces in a humansubject group an average AUC_((0-∞)) of cromolyn sodium greater thanabout 330 ng*hr/mL. In some embodiments wherein the mast cell stabilizeris cromolyn sodium, administration of a composition with an inhalationdevice provides a bioavailability of the mast cell stabilizer greaterthan about 5% and produces in a human subject group an averageAUC_((0-∞)) of cromolyn sodium greater than about 525 ng*hr/mL. In someembodiments wherein the mast cell stabilizer is cromolyn sodium,administration of a composition with an inhalation device produces in ahuman subject group an average AUC_((0-∞)) of cromolyn sodium greaterthan about 120 ng*hr/mL, and the composition has an RF (≤3.3 μm) of atleast about 30%. In some embodiments wherein the mast cell stabilizer iscromolyn sodium, administration of a composition with an inhalationdevice produces in a human subject group an average AUC_((0-∞)) ofcromolyn sodium greater than about 200 ng*hr/mL, and the composition hasan RF (≤3.3 μm) of at least about 30%. In some embodiments wherein themast cell stabilizer is cromolyn sodium, administration of a compositionwith an inhalation device produces in a human subject group an averageAUC_((0-∞)) of cromolyn sodium greater than about 330 ng*hr/mL, and thecomposition has an RF (≤3.3 μm) of at least about 40%. In someembodiments wherein the mast cell stabilizer is cromolyn sodium,administration of a composition with an inhalation device produces in ahuman subject group an average AUC_((0-∞)) of cromolyn sodium greaterthan about 525 ng*hr/mL, and the composition has an RF (≤3.3 μm) of atleast about 40%. In some embodiments the composition administered withan inhalation device is not co-administered with an oral formulation ofcromolyn sodium.

DETAILED DESCRIPTION OF THE INVENTION

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of skill in the artto which the inventions described herein belong. All publications,patents, and patent applications mentioned in this specification arehereby incorporated by reference to the same extent as if eachindividual publication, patent, or patent application was specificallyand individually indicated to be incorporated by reference.

Definition of Terms

As used herein, the term “about” is used synonymously with the term“approximately.” Illustratively, the use of the term “about” with regardto a certain therapeutically effective pharmaceutical dose indicatesthat values slightly outside the cited values, e.g., plus or minus 0.1%to 10%, are also effective and safe.

As used herein, the terms “comprising,” “including,” “such as,” and “forexample” (or “e.g.”) are used in their open, non-limiting sense.

As used herein, the phrase “consisting essentially of” is a transitionalphrase used in a claim to indicate that the following list ofingredients, parts or process steps must be present in the claimedcomposition, machine or process, but that the claim is open to unlistedingredients, parts or process steps that do not materially affect thebasic and novel properties of the invention.

“Nominal dose,” as used herein, refers to the loaded dose, which is theamount of mast cell stabilizer in an inhalation device prior toadministration to the patient. The volume of solution containing thenominal dose is referred to as the “fill volume.”

“AUC_(last)” as used herein refers to the area under the curve from timezero to time of last measurable concentration of active pharmaceuticalingredient (API).

“AUC_(last) ^(HEN)” as used herein refers to the area under a bloodplasma concentration curve up to the last time point for the nominaldose of active pharmaceutical ingredient (API) administered with a highefficiency nebulizer.

“AUC_(last) ^(Conv)” as used herein refers to the area under a bloodplasma concentration curve up to the last time point for a nominal doseof active pharmaceutical ingredient (API) administered with aconventional inhalation device.

“AUC_((0-∞))” as used herein refers to the total area under a bloodplasma concentration curve for an active pharmaceutical ingredient(API).

“AUC_((0-∞)) ^(HEN)” as used herein refers to the total area under ablood plasma concentration curve for a nominal dose of activepharmaceutical ingredient (API) administered with a high efficiencynebulizer.

“AUC_((0-∞)) ^(Conv)” as used herein refers to the total area under ablood plasma concentration curve for a nominal dose of activepharmaceutical ingredient (API) administered with a conventionalinhalation device.

AUC_((0-∞)) can be determined by methods known to those of skill in theart. For example, the AUC_((0-∞)) of an API can be determined bycollecting blood samples from a subject at various time points afteradministration of an API to the subject, separating plasma from theblood samples, extracting the API from the separated plasma samples,e.g., by solid-phase extraction, quantifying the amount of the APIextracted from each sample of separated plasma, e.g., by liquidchromatography-tandem mass spectrometry (LC-MS/MS), plotting theconcentration of API in each sample versus the time of collection afteradministration, and calculating the area under the curve.

“Substantially the same nominal dose” as used herein means that a firstnominal dose of an active pharmaceutical ingredient (API) containsapproximately the same number of millimoles of the mast cell stabilizeras a second nominal dose of the mast cell stabilizer.

“Bioavailability” as used herein refers to the amount of unchanged APIthat reaches the systemic circulation, expressed as a percentage of thedosage of the API that is administered to a subject. By definition, thebioavailability of an intravenous solution containing the activepharmaceutical ingredient (API) is 100%. The bioavailability of an APIcan be determined by methods known to those of skill in the art. Forexample, the bioavailability of an API can be determined by collectingurine samples from a subject at various time points followingadministration of the API to the subject, extracting the API from theurine samples, e.g., by solid-phase extraction, quantifying the amountof the API in each urine sample, adjusting the amount of API collectedfrom the urine by a factor based on the amount of API reaching systemiccirculation that is excreted in the urine, and calculating thepercentage of the API administered to the subject that reaches thesystemic circulation of the subject. In a specific embodiment, thebioavailability of cromolyn sodium can be determined as described inWalker et al., 24 J. Pharm. Pharmacol. 525-31 (1972). In the case ofcromolyn sodium, the amount of the compound isolated from the urine ismultiplied by two to calculate the total amount reaching systemiccirculation after administration because the compound is known to beexcreted unmetabolized in equal parts in the urine and feces, i.e.,approximately 50% of the amount of cromolyn sodium that reaches systemiccirculation is excreted in the urine and approximately 50% of the amountof cromolyn sodium that reaches systemic circulation is excreted in thefeces.

“Enhanced lung deposition” as used herein refers to an increase in drugdeposition (deposited lung dose) arising out of, for example, improvedefficiency of drug delivery.

“Deposited dose” or “deposited lung dose” is the amount of mast cellstabilizer deposited in the lung. The deposited dose or deposited lungdose may be expressed in absolute terms, for example in mg or μg of APIdeposited in the lungs. The deposited lung dose may also be expressed inrelative terms, for example calculating the amount of API deposited as apercentage of the nominal dose.

“C_(max)” as used herein refers to the maximum plasma concentration foran active pharmaceutical ingredient (API).

“C_(max) ^(HEN)” as used herein refers to the maximum blood plasmaconcentration for a nominal dose of the active pharmaceutical ingredient(API) administered with a high efficiency nebulizer.

“C_(max) ^(Conv)” as used herein refers to the maximum blood plasmaconcentration for a nominal dose of the active pharmaceutical ingredient(API) administered with a conventional inhalation device.

C_(max) can be determined by methods known to those of skill in the art.For example, the C_(max) of an API can be determined by collecting bloodsamples from a subject at various time points after administration of anAPI to the subject, separating plasma from the blood samples, extractingthe API from the separated plasma samples, e.g., by solid-phaseextraction, quantifying the amount of the API extracted from each sampleof separated plasma, e.g., by LC-MS/MS, plotting the concentration ofAPI in each sample versus the time of collection after administration,and identifying the peak concentration of the API on the curve.

“Enhanced pharmacokinetic profile” means an improvement in somepharmacokinetic parameter. Pharmacokinetic parameters that may beimproved include AUC (0-4 or 0-6 or 0-8 h), AUC_(last), AUC_((0-∞)),T_(max), T_(1/2), and C_(max). In some embodiments, the enhancedpharmacokinetic profile may be measured quantitatively by comparing apharmacokinetic parameter obtained for a nominal dose of an activepharmaceutical ingredient (API) administered by one route ofadministration, such as an inhalation device (e.g., a high efficiencynebulizer) with the same pharmacokinetic parameter obtained with thesame nominal dose of active pharmaceutical ingredient (API) administeredby a different route of administration, such as a different type ofinhalation device or an oral formulation (e.g., oral tablet, oralcapsule, or oral solution).

“Blood plasma concentration” refers to the concentration of an activepharmaceutical ingredient (API) in the plasma component of blood of asubject or patient population.

“Patient” or “subject” refers to the animal (especially mammal) or humanbeing treated.

A “subject group” or “patient group” has a sufficient number of subjectsor patients to provide a statistically significant average measurementof the relevant pharmacokinetic parameter. All members of the “subjectgroup” or “patient group” have pharmacokinetic parameters for the mastcell stabilizers that fall within statistically normal ranges (i.e.,there are no outliers), and no member is included on the basis ofnon-standard or unusual measurements.

“Nebulizer,” as used herein, refers to a device that turns medications,compositions, formulations, suspensions, and mixtures, etc. into a fineaerosol mist for delivery to the lungs.

“Drug absorption” or simply “absorption” typically refers to the processof movement of drug from site of delivery of a drug across a barrierinto a blood vessel or the site of action, e.g., a drug being absorbedvia the pulmonary capillary beds of the alveoli into the systemiccirculation.

“T_(max)” as used herein refers to the amount of time necessary for anactive pharmaceutical ingredient (API) to attain maximum blood plasmaconcentration.

“T_(max) ^(HEN)” as used herein refers to the amount of time necessaryfor a nominal dose of an active pharmaceutical ingredient (API) toattain maximum blood plasma concentration after administration with ahigh efficiency nebulizer.

“T_(max) ^(Conv)” as used herein refers to the amount of time necessaryfor a nominal dose of an active pharmaceutical ingredient (API) toattain maximum blood plasma concentration after administration with aconventional inhalation device.

The term “treat” and its grammatical variants (e.g., “to treat,”“treating,” and “treatment”) refer to administration of an activepharmaceutical ingredient to a patient with the purpose of amelioratingor reducing the incidence of one or more symptoms of a condition ordisease state in the patient. Such symptoms may be chronic or acute; andsuch amelioration may be partial or complete. In the present context,treatment entails administering a mast cell stabilizer to a patient viaany route of administration disclosed herein.

As used herein, the term “high concentration” refers to a concentrationgreater than 1% by weight. For example, in a specific embodiment, a“high concentration” formulation of cromolyn sodium comprises cromolynsodium at a concentration of greater than 1% by weight.

As used herein, the term “hypotonic” refers to a formulation that has atonicity less than 295 mOsm/kg.

The term “prophylaxis” refers to administration of an activepharmaceutical ingredient to a patient with the purpose of reducing theoccurrence or recurrence of one or more acute symptoms associated with adisease state or a condition in the patient. In the present context,prophylaxis entails administering a mast cell stabilizer to a patientvia any route of administration disclosed herein. Thus, prophylaxisincludes reduction in the occurrence or recurrence rate of a systemicmast cell related disorder. However, prophylaxis is not intended toinclude complete prevention of onset of a disease state or a conditionin a patient who has not previously been identified as suffering fromthe disease or the condition.

As used herein, a “systemically effective amount” is an amount of mastcell stabilizer in the body of a patient as a whole that is effectivefor the treatment or prophylaxis of a systemic mast cell relateddisorder. A “systemically effective amount” may be expressed, forexample, as the mass of a mast cell stabilizer, or concentration of amast cell stabilizer, in a patient's plasma. A “systemically effectiveamount” may differ depending on the specific mast cell stabilizer andthe specific systemic mast cell related disorder.

As used herein, a difference is “significant” if a person skilled in theart would recognize that the difference is probably real. In someembodiments, significance may be determined statistically, in which casetwo measured parameters may be referred to as statistically significant.In some embodiments, statistical significance may be quantified in termsof a stated confidence interval (CI), e.g., greater than 90%, greaterthan 95%, greater than 98%, etc. In some embodiments, statisticalsignificance may be quantified in terms of a p value, e.g., less than0.5, less than 0.1, less than 0.05, etc. The person skilled in the artwill recognize these expressions of significance and will know how toapply them appropriately to the specific parameters that are beingcompared.

Methods of Treating Systemic Mast Cell Related Disorders with Mast CellStabilizers

Disclosed herein are methods for the treatment or prophylaxis ofsystemic mast cell related disorders comprising administeringcompositions comprising one or more mast cell stabilizers. As usedherein, a “systemic mast cell related disorder” is a disease orcondition that is caused by or associated with excessive proliferationor activation of mast cells or abnormal release of vasoactive orpro-inflammatory mediators in the body as a whole, and is thus treatableby administration of a systemically effective amount of a mast cellstabilizer, e.g., cromolyn sodium. A systemic mast cell related disorderis distinct from a local mast cell related disorder, in which symptomsof the disease or condition manifest in a particular region of the body.Systemic mast cell related disorders include, but are not limited to, amast cell activation syndrome; mastocytosis; idiopathic urticaria;chronic urticaria; atopic dermatitis; idiopathic anaphylaxis; Ig-E andnon Ig-E mediated anaphylaxis; angioedema; allergic disorders; irritablebowel syndrome; mastocytic gastroenteritis; mastocytic colitis;fibromyalgia; kidney fibrosis; atherosclerosis; myocardial ischemia;hypertension; congestive heart failure; pruritus; chronic pruritus;pruritus secondary to chronic kidney failure; heart, vascular,intestinal, brain, kidney, liver, pancreas, muscle, bone and skinconditions associated with mast cells; CNS diseases such as Parkinson'sdisease and Alzheimer's disease; metabolic diseases such as diabetes;sickle cell disease; autism; chronic fatigue syndrome; lupus; chroniclyme disease; interstitial cystitis; multiple sclerosis; cancer;migraine headaches; psoriasis; eosinophilic esophagitis; eosinophilicgastroenteritis; Churg-Strauss syndrome; hypereosinophilic syndrome;eosinophilic fasciitis; eosinophilic gastrointestinal disorders; chronicidiopathic urticaria; myocarditis; Hirschsprung's-associatedenterocolitis; postoperative ileus; wound healing; stroke; transientischemic attack; pain; neuralgia; peripheral neuropathy; acute coronarysyndromes; pancreatitis; cutaneous mastocytosis; systemic mastocytosis;systemic indolent mastocytosis; dermatomyositis; fibrotic skin diseases;pain associated with cancer; ulcerative colitis; inflammatory boweldisease; radiation colitis; celiac disease; gluten enteropathy;radiation cystitis; painful bladder syndrome; hepatitis; hepaticfibrosis; cirrhosis; rheumatoid arthritis; lupus erythematosus; andvasculitis.

In some embodiments of the methods disclosed herein wherein the systemicmast cell related disorder is a CNS disease such as Parkinson's diseaseand Alzheimer's disease, a mast cell stabilizer is neuroprotective. Insome embodiments of the methods disclosed herein wherein the systemicmast cell related disorder is a CNS disease such as Parkinson's diseaseand Alzheimer's disease, a mast cell stabilizer crosses the blood brainbarrier. In some embodiments of the methods disclosed herein wherein thesystemic mast cell related disorder is Alzheimer's disease, a mast cellstabilizer prevents amyloid-beta protein polymerization and/or plaqueformation. In some embodiments of the methods disclosed herein whereinthe systemic mast cell related disorder is a heart condition, a mastcell stabilizer is cardioprotective.

In some embodiments of the methods disclosed herein, a compositioncomprising a mast cell stabilizer is administered for the treatment orprophylaxis of a condition that is associated with a systemic mast cellrelated disorder, including but not limited to autoimmune disorders,inflammatory conditions, allergic diseases and conditions, and viral andbacterial infections.

In some embodiments of the methods disclosed herein, the number of mastcells in a patient is stabilized after administration of a compositioncomprising a mast cell stabilizer to the patient. In some embodiments ofthe methods disclosed herein, the activity of mast cells is stabilizedin a patient after administration of a composition comprising a mastcell stabilizer to the patient. In some embodiments of the methodsdisclosed herein, one or more of total tryptase and histamine in apatient's blood, and prostaglandin D2, 11beta-prostaglandin F2-alpha,and N-methylhistamine in the patient's urine, is reduced afteradministration of a composition comprising a mast cell stabilizer to apatient.

As used herein, a “mast cell stabilizer” refers to an agent thatinhibits degranulation and/or the release of pro-inflammatory andvasoactive mediators from mast cells. Mast cell stabilizers include, butare not limited to, cromolyn, dihydropyridines such as nicardipine andnifedipine, lodoxamide, nedocromil, barnidipine, YC-114, elgodipine,niguldipine, ketotifen, methylxanthines, quercetin, and pharmaceuticallysalts thereof. In some embodiments, the mast cell stabilizer is apharmaceutically acceptable salt of cromolyn, such as cromolyn sodium,cromolyn lysinate, ammonium cromonglycate, and magnesium cromoglycate.In some embodiments, mast cell stabilizers include but are not limitedto compounds disclosed in U.S. Pat. Nos. 6,207,684; 4,634,699;6,207,684; 4,871,865; 4,923,892; 6,225,327; 7,060,827; 8,470,805;5,618,842; 5,552,436; 5,576,346; 8,252,807; 8,088,935; 8,617,517;4,268,519; 4,189,571; 3,790,580; 3,720,690; 3,777,033; 4,067,992;4,152,448; 3,419,578; 4,847,286; 3,683,320; and 4,362,742; U.S. PatentApplication Publication Nos. 2011/112183 and 2014/140927; EuropeanPatent Nos. 2391618; 0163683; 0413583; and 0304802; International PatentApplication Nos. WO2010/042504; WO85/02541; WO2014/115098;WO2005/063732; WO2009/131695; and WO2010/088455; all of which areincorporated by reference. Mast cell stabilizers, including cromolyn andpharmaceutically acceptable salts, prodrugs, and adducts thereof, may beprepared by methods known in the art.

In some embodiments, mast cell stabilizers described herein may beprepared as prodrugs. A “prodrug” refers to an agent that is convertedinto the parent drug in vivo. The prodrug can be designed to alter themetabolic stability or the transport characteristics of a drug, to maskside effects or toxicity, to improve the flavor of a drug, or to alterother characteristics or properties of a drug. In some embodiments, theprodrug has improved bioavailability relative to the parent drug. Insome embodiments, the prodrug has improved solubility in pharmaceuticalcompositions over the parent drug. In some embodiments, prodrugs may bedesigned as reversible drug derivatives, for use as modifiers to enhancedrug transport to site-specific tissues. In some embodiments, a prodrugof a mast cell stabilizer is an ester of the mast cell stabilizer, whichis hydrolyzed to the carboxylic acid, the parent mast cell stabilizer.In some embodiments, a prodrug comprises a short peptide (polyaminoacid)bonded to an acid group, wherein the peptide is metabolized in vivo toreveal the parent drug. In certain embodiments, upon in vivoadministration, a prodrug is chemically converted to the biologically,pharmaceutically or therapeutically active form of the mast cellstabilizer. In certain embodiments, a prodrug is enzymaticallymetabolized by one or more steps or processes to the parent mast cellstabilizer. In certain embodiments, the mast cell stabilizer is aprodrug of cromolyn. In a specific embodiment, the prodrug of cromolynis cromoglicate lisetil.

To produce a prodrug, a pharmaceutically active mast cell stabilizercompound is modified such that the active compound will be regeneratedupon in vivo administration. In some embodiments, prodrugs of mast cellstabilizers are designed by virtue of knowledge of pharmacodynamicprocesses and drug metabolism in vivo. See, e.g., Nogrady (1985)Medicinal Chemistry A Biochemical Approach, Oxford University Press, NewYork, pages 388-392; Silverman (1992), The Organic Chemistry of DrugDesign and Drug Action, Academic Press, Inc., San Diego, pages 352-401,Saulnier et al., (1994), Bioorganic and Medicinal Chemistry Letters,Vol. 4, p. 1985; Rooseboom et al., Pharmacological Reviews, 56:53-102,2004; Miller et al., J. Med. Chem. Vol. 46, no. 24, 5097-5116, 2003;Aesop Cho, “Recent Advances in Oral Prodrug Discovery”, Annual Reportsin Medicinal Chemistry, Vol. 41, 395-407, 2006.

In some embodiments, mast cell stabilizers described herein includeisotopically-labeled compounds, which are identical to those recitedherein, but for the fact that one or more atoms are replaced by an atomhaving an atomic mass or mass number different from the atomic mass ormass number usually found in nature. Examples of isotopes that can beincorporated into the present compounds include isotopes of hydrogen,carbon, nitrogen, oxygen, fluorine and chlorine, such as, for example,²H, ³H, ¹³C, ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O, ³⁵S, ¹⁸F, ³⁶Cl, respectively. Certainisotopically labeled compounds described herein, for example those withisotopes such as deuterium, i.e., ²H, can afford certain therapeuticadvantages resulting from greater metabolic stability, such as, forexample, increased in vivo half-life or reduced dosage requirements. Incertain embodiments, the mast cell stabilizer is isotopically labeledcromolyn, or a pharmaceutically acceptable salt thereof, such ascromolyn sodium. In some embodiments, the mast cell stabilizer isdeuterium-labeled cromolyn sodium.

In some embodiments, mast cell stabilizers described herein may bePEGylated, wherein one or more polyethylene glycol (PEG) polymers arecovalently attached to the mast cell stabilizers. In some embodiments,pegylated mast cell stabilizers increase the half-life of the mast cellstabilizers in the body. In some embodiments, pegylation of the mastcell stabilizers increases the hydrodynamic size of the mast cellstabilizers and reduces their renal clearance. In some embodiments,pegylation of the mast cell stabilizers increases the solubility of themast cell stabilizers. In some embodiments, pegylation of the mast cellstabilizers protects the mast cell stabilizers from proteolyticdegradation.

Mast cell stabilizers may be administered in the methods disclosedherein in a suitable dose or nominal dose as determined by one ofordinary skill in the art. In some embodiments, the mast cell stabilizeris administered at a dosage or nominal dosage of less than about 1mg/dose, about 1 mg/dose to about 100 mg/dose, about 1 mg/dose to about120 mg/dose, about 5 mg/dose to about 80 mg/dose, about 20 mg/dose toabout 60 mg/dose, about 30 mg/dose to about 50 mg/dose, or greater thanabout 100 mg/dose. In some embodiments, the mast cell stabilizer isadministered in less than about 1 mg, about 1 mg, about 5 mg, about 10mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg,about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg,about 95 mg, about 100 mg, about 105 mg, about 110 mg, about 115 mg,about 120 mg, about 125 mg, about 130 mg doses, about 135 mg, about 140mg, about 145 mg, about 150 mg, about 200 mg, about 250 mg, about 300mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550mg, about 600 mg, about 650 mg, about 700 mg, about 750 mg, about 800mg, about 850 mg, about 900 mg, about 950 mg, or about 1000 mg doses.

In some embodiments of the methods disclosed herein, cromolyn sodium isadministered at a dosage or nominal dosage of less than about 1 mg/dose,about 1 mg/dose to about 100 mg/dose, about 1 mg/dose to about 120mg/dose, about 5 mg/dose to about 80 mg/dose, about 20 mg/dose to about60 mg/dose, or about 30 mg/dose to about 50 mg/dose, or greater thanabout 100 mg/dose. In other embodiments, cromolyn sodium is administeredin less than about 1 mg, about 1 mg, about 5 mg, about 10 mg, about 15mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg,about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg,about 100 mg, about 105 mg, about 110 mg, about 115 mg, about 120 mg,about 125 mg, about 130 mg doses, about 135 mg, about 140 mg, about 145mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 350mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600mg, about 650 mg, about 700 mg, about 750 mg, about 800 mg, about 850mg, about 900 mg, about 950 mg, or about 1000 mg doses.

In some embodiments of the methods disclosed herein, further activeagents other than a mast cell stabilizer that are effective for thetreatment or prophylaxis of a systemic mast cell related disorder areadministered or co-administered with the mast cell stabilizer. Suchfurther active agents may be administered separately, or may beincorporated into a composition comprising a mast cell stabilizer. Suchfurther active agents include, but are not limited to, leukotrieneantagonists, steroidal and non-steroidal anti-inflammatory drugs,anti-allergics, β-agonists, anticolinergics, corticosteroids,testosterone derivatives, phosphodiesterase inhibitors, endothelinantagonists, mucolytics, antibiotics, antifungals, antivirals,antioxidants, vitamins, heparinoids, α-antitrypsin, lung surfactants,anti-inflammatory compounds, glucocorticoids, anti-infective agents,antibiotics, antifungals, antivirals, antiseptics, vasoconstrictors,vasodilators, wound healing agents, local anesthetics, peptides, andproteins.

Anti-inflammatory compounds which may be administered or co-administeredwith a mast cell stabilizer in the methods disclosed herein include butare not limited to betamethasone, beclomethasone, budesonide,ciclesonide, dexamethasone, desoxymethasone, fluoconolone acetonide,flucinonide, flunisolide, fluticasone, icomethasone, rofleponide,triamcinolone acetonide, fluocortin butyl, hydrocortisone,hydroxycortisone-17-butyrate, prednicarbate, 6-methylprednisoloneaceponate, mometasone furoate, elastane-, prostaglandin-, leukotriene,bradykinin-antagonists, non-steroidal anti-inflammatory drugs (NSAIDs),such as ibuprofen and indometacin.

Anti-allergic agents which may be administered or co-administered with amast cell stabilizer in the methods disclosed herein include but are notlimited to glucocorticoids, nedocromil, cetirizine, loratidine,montelukast, roflumilast, ziluton, omalizumab, heparins and heparinoidsand other antihistamines, azelastine, cetirizine, desloratadine,ebastine, fexofenadine, levocetirizine, loratadine.

Anti-infective agents which may be administered or co-administered witha mast cell stabilizer in the methods disclosed herein include but arenot limited to benzylpenicillins (penicillin-G-sodium, clemizonepenicillin, benzathine penicillin G), phenoxypenicillins (penicillin V,propicillin), aminobenzylpenicillins (ampicillin, amoxycillin,bacampicillin), acylaminopenicillins (azlocillin, mezlocillin,piperacillin, apalcillin), carboxypenicillins (carbenicillin,ticarcillin, temocillin), isoxazolyl penicillins (oxacillin,cloxacillin, dicloxacillin, flucloxacillin), and amidine penicillins(mecillinam); cephalosporins, including cefazolins (cefazolin,cefazedone); cefuroximes (cefuroxime, cefamandole, cefotiam), cefoxitins(cefoxitin, cefotetan, latamoxef, flomoxef), cefotaximes (cefotaxime,ceftriaxone, ceftizoxime, cefinenoxime), ceftazidimes (ceftazidime,cefpirome, cefepime), cefalexins (cefalexin, cefaclor, cefadroxil,cefradine, loracarbef, cefprozil), and cefiximes (cefixime, cefpodoximproxetile, cefuroxime axetil, cefetamet pivoxil, cefotiam hexetil),loracarbef, cefepim, clavulanic acid/amoxicillin, ceftobiprole;synergists, including beta-lactamase inhibitors, such as clavulanicacid, sulbactam, and tazobactam; carbapenems, including imipenem,cilastin, meropenem, doripenem, tebipenem, ertapenem, ritipenam, andbiapenem; monobactams, including aztreonam; aminoglycosides, such asapramycin, gentamicin, amikacin, isepamicin, arbekacin, tobramycin,netilmicin, spectinomycin, streptomycin, capreomycin, neomycin,paromoycin, and kanamycin; macrolides, including erythromycin,clarythromycin, roxithromycin, azithromycin, dithromycin, josamycin,spiramycin and telithromycin; gyrase inhibitors or fluoroquinolones,including ciprofloxacin, gatifloxacin, norfloxacin, ofloxacin,levofloxacin, perfloxacin, lomefloxacin, fleroxacin, garenoxacin,clinafloxacin, sitafloxacin, prulifloxacin, olamufloxacin,caderofloxacin, gemifloxacin, balofloxacin, trovafloxacin, andmoxifloxacin; tetracyclins, including tetracyclin, oxytetracyclin,rolitetracyclin, minocyclin, doxycycline, tigecycline and aminocycline;glycopeptides, including vancomycin, teicoplanin, ristocetin, avoparcin,oritavancin, ramoplanin, and peptide 4; polypeptides, includingplectasin, dalbavancin, daptomycin, oritavancin, ramoplanin,dalbavancin, telavancin, bacitracin, tyrothricin, neomycin, kanamycin,mupirocin, paromomycin, polymyxin B and colistin; sulfonamides,including sulfadiazine, sulfamethoxazole, sulfalene, co-trimoxazole,co-trimetrol, co-trimoxazine, and co-tetraxazine; azoles, includingclotrimazole, oxiconazole, miconazole, ketoconazole, itraconazole,fluconazole, metronidazole, tinidazole, bifonazole, ravuconazole,posaconazole, voriconazole, and ornidazole and other antifungalsincluding flucytosin, griseofluvin, tonoftal, naftifine, terbinafine,amorolfine, ciclopiroxolamin, echinocandins, such as micafungin,caspofungin, anidulafungin; nitrofurans, including nitrofurantoin andnitrofuranzone; polyenes, including amphotericin B, natamycin, nystatin,flucocytosine; other antibiotics, including tithromycin, lincomycin,clindamycin, oxazolidinones (linezolids), ranbezolid, streptogramineA+B, pristinamycin A+B, virginiamycin A+B, dalfopristin/quinupristin(Synercid), chloramphenicol, ethambutol, pyrazinamide, terizidon,dapson, prothionamide, fosfomycin, fucidinic acid, rifampicine,isoniazid, cycloserine, terizidone, ansamycin, lysostaphin, iclaprim,mirocin B17, clerocidin, filgrastim, and pentamidine; antivirals,including aciclovir, ganciclovir, birivudine, valaciclovir, zidovudine,didanosine, thiacytidin, stavudine, lamivudine, zalcitabine, ribavirin,nevirapirine, delaviridine, trifluridine, ritonavir, saquinavir,indinavir, foscarnet, amantadine, podophyllotoxin, vidarabine,tromantadine, and proteinase inhibitors; plant extracts or ingredients,such as plant extracts from chamomile, hamamelis, echinacea, calendula,papain, pelargonium, essential oils, myrtol, pinen, limonen, cineole,thymol, mentol, tee tree oil, alpha-hederin, bisabolol, lycopodin,vitapherole; wound healing compounds including dexpantenol, allantoin,vitamins, hyaluronic acid, alpha-antitrypsin, inorganic and organic zincsalts/compounds, interferones (alpha, beta, gamma), tumor necrosisfactors, cytokines, interleukins.

Mucolytics which may be administered or co-administered with a mast cellstabilizer in the methods disclosed herein include but are not limitedto DNase, P2Y2-agonists (denufosol), heparinoids, guaifenesin,acetylcysteine, carbocysteine, ambroxol, bromhexine, lecithins, myrtol,and recombinant surfactant proteins.

Local anesthetic agents which may be administered or co-administeredwith a mast cell stabilizer in the methods disclosed herein include butare not limited to benzocaine, tetracaine, procaine, lidocaine andbupivacaine.

Peptides and proteins which may be administered or co-administered witha mast cell stabilizer in the methods disclosed herein include but arenot limited to antibodies against toxins produced by microorganisms,antimicrobial peptides such as cecropins, defensins, thionins, andcathelicidins.

Immunomodulators which may be administered or co-administered with amast cell stabilizer in the methods disclosed herein include but are notlimited to methotrexate, azathioprine, cyclosporine A, tacrolimus,sirolimus, rapamycin, mycophenolate, mofetil, cytostatics and metastasisinhibitors, alkylants, such as nimustine, melphanlane, carmustine,lomustine, cyclophosphosphamide, ifosfamide, trofosfamide, chlorambucil,busulfane, treosulfane, prednimustine, thiotepa; antimetabolites, e.g.cytarabine, fluorouracil, methotrexate, mercaptopurine, tioguanine;alkaloids, such as vinblastine, vincristine, vindesine; antibiotics,such as alcarubicine, bleomycine, dactinomycin, daunorubicine,doxorubicine, epirubicine, idarubicine, mitomycine, plicamycine;complexes of secondary group elements (e.g. Ti, Zr, V, Nb, Ta, Mo, W,Pt) such as carboplatinum, cis-platinum and metallocene compounds suchas titanocendichloride; amsacrine, dacarbazine, estramustine, etoposide,beraprost, hydroxycarbamide, mitoxanthrone, procarbazine, temiposide;paclitaxel, iressa, zactima, poly-ADP-ribose-polymerase (PRAP) enzymeinhibitors, banoxantrone, gemcitabine, pemetrexed, bevacizumab,ranibizumab.

Proteinase inhibitors which may be administered or co-administered witha mast cell stabilizer in the methods disclosed herein include but arenot limited to alpha-anti-trypsin; antioxidants, such as tocopherols,glutathion; pituitary hormones, hypothalamic hormones, regulatorypeptides and their inhibiting agents, corticotropine, tetracosactide,choriogonandotropine, urofolitropine, urogonadotropine, somatotropine,metergoline, desmopressine, oxytocine, argipressine, ornipressine,leuproreline, triptoreline, gonadoreline, busereline, nafareline,goselerine, somatostatine; parathyroid gland hormones, calciummetabolism regulators, dihydrotachysterole, calcitonine, clodronic acid,etidronic acid; thyroid gland therapeutics; sex hormones and theirinhibiting agents, anabolics, androgens, estrogens, gestagenes,antiestrogenes; anti-migraine drugs, such as proxibarbal, lisuride,methysergide, dihydroergotamine, ergotamine, clonidine, pizotifene;hypnotics, sedatives, benzodiazepines, barbiturates, cyclopyrrolones,imidazopyridines, antiepileptics, zolpidem, barbiturates, phenyloin,primidone, mesuximide, ethosuximide, sultiam, carbamazepin, valproicacid, vigabatrin; antiparkinson drugs, such as levodopa, carbidopa,benserazide, selegiline, bromocriptine, amantadine, tiapride;antiemetics, such as thiethylperazine, bromopride, domperidone,granisetrone, ondasetrone, tropisetrone, pyridoxine; analgesics, such asbuprenorphine, fentanyl, morphine, codeine, hydromorphone, methadone;fenpipramide, fentanyl, piritramide, pentazocine, buprenorphine,nalbuphine, tilidine; drugs for narcosis, such as N-methylatedbarbiturates, thiobarbiturates, ketamine, etomidate, propofol,benzodiazepines, droperidol, haloperidol, alfentanyl, sulfentanyl;antirheumatism drugs including tumor necrosis factor-alfa, nonsteroidalantiinflammatory drugs; antidiabetic drugs, such as insulin,sulfonylurea derivatives, biguanids, glitizols, glucagon, diazoxid;cytokines, such as interleukines, interferones, tumor necrosis factor(TNF), colony stimulating factors (GM-CSF, G-CSF, M-CSF); proteins, e.g.epoetine, and peptides, e.g. parathyrin, somatomedin C; heparine,heparinoids, urokinases, streptokinases, ATP-ase, prostacycline, sexualstimulants, and genetic material.

Formulations for the Administration of Mast Cell Stabilizers

In some embodiments, formulations administered in the methods disclosedherein produce in a human subject group an average AUC_((0-∞)) of a mastcell stabilizer greater than about 100 ng*hr/mL, greater than about 110ng*hr/mL, greater than about 120 ng*hr/mL, greater than about 130ng*hr/mL, greater than about 140 ng*hr/mL, greater than about 150ng*hr/mL, greater than about 160 ng*hr/mL, greater than about 170ng*hr/mL, greater than about 180 ng*hr/mL, greater than about 190ng*hr/mL, greater than about 200 ng*hr/mL, greater than about 225ng*hr/mL, greater than about 250 ng*hr/mL, greater than about 275ng*hr/mL, greater than about 300 ng*hr/mL, greater than about 325ng*hr/mL, greater than about 350 ng*hr/mL, greater than about 375ng*hr/mL, greater than about 400 ng*hr/mL, greater than about 425ng*hr/mL, greater than about 450 ng*hr/mL, greater than about 475ng*hr/mL, greater than about 500 ng*hr/mL, greater than about 525ng*hr/mL, greater than about 550 ng*hr/mL, greater than about 575ng*hr/mL, greater than about 600 ng*hr/mL, greater than about 625ng*hr/mL, greater than about 650 ng*hr/mL, greater than about 675ng*hr/mL, greater than about 700 ng*hr/mL, greater than about 725ng*hr/mL, greater than about 750 ng*hr/mL, greater than about 775ng*hr/mL, greater than about 800 ng*hr/mL, greater than about 825ng*hr/mL, greater than about 850 ng*hr/mL, greater than about 875ng*hr/mL, greater than about 900 ng*hr/mL, greater than about 925ng*hr/mL, greater than about 950 ng*hr/mL, greater than about 975ng*hr/mL, or greater than about 1000 ng*hr/mL after administration ofthe formulation to the patient. In some embodiments, formulationsadministered in the methods disclosed herein produce in a human subjectgroup an average AUC_((0-∞)) of a mast cell stabilizer of about 100ng*hr/mL, about 110 ng*hr/mL, about 120 ng*hr/mL, about 130 ng*hr/mL,about 140 ng*hr/mL, about 150 ng*hr/mL, about 160 ng*hr/mL, about 170ng*hr/mL, about 180 ng*hr/mL, about 190 ng*hr/mL, about 200 ng*hr/mL,about 225 ng*hr/mL, about 250 ng*hr/mL, about 275 ng*hr/mL, about 300ng*hr/mL, about 325 ng*hr/mL, about 350 ng*hr/mL, about 375 ng*hr/mL,about 400 ng*hr/mL, about 425 ng*hr/mL, about 450 ng*hr/mL, about 475ng*hr/mL, about 500 ng*hr/mL, about 525 ng*hr/mL, about 550 ng*hr/mL,about 575 ng*hr/mL, about 600 ng*hr/mL, about 625 ng*hr/mL, about 650ng*hr/mL, about 675 ng*hr/mL, about 700 ng*hr/mL, about 725 ng*hr/mL,about 750 ng*hr/mL, about 775 ng*hr/mL, about 800 ng*hr/mL, about 825ng*hr/mL, about 850 ng*hr/mL, about 875 ng*hr/mL, about 900 ng*hr/mL,about 925 ng*hr/mL, about 950 ng*hr/mL, about 975 ng*hr/mL, or about1000 ng*hr/mL after administration of the formulation to the patient.

In some embodiments, formulations administered in the methods disclosedherein produce in a human subject group an average AUC_((0-∞)) ofcromolyn sodium greater than about 100 ng*hr/mL, greater than about 110ng*hr/mL, greater than about 120 ng*hr/mL, greater than about 130ng*hr/mL, greater than about 140 ng*hr/mL, greater than about 150ng*hr/mL, greater than about 160 ng*hr/mL, greater than about 170ng*hr/mL, greater than about 180 ng*hr/mL, greater than about 190ng*hr/mL, greater than about 200 ng*hr/mL, greater than about 225ng*hr/mL, greater than about 250 ng*hr/mL, greater than about 275ng*hr/mL, greater than about 300 ng*hr/mL, greater than about 325ng*hr/mL, greater than about 350 ng*hr/mL, greater than about 375ng*hr/mL, greater than about 400 ng*hr/mL, greater than about 425ng*hr/mL, greater than about 450 ng*hr/mL, greater than about 475ng*hr/mL, greater than about 500 ng*hr/mL, greater than about 525ng*hr/mL, greater than about 550 ng*hr/mL, greater than about 575ng*hr/mL, greater than about 600 ng*hr/mL, greater than about 625ng*hr/mL, greater than about 650 ng*hr/mL, greater than about 675ng*hr/mL, greater than about 700 ng*hr/mL, greater than about 725ng*hr/mL, greater than about 750 ng*hr/mL, greater than about 775ng*hr/mL, greater than about 800 ng*hr/mL, greater than about 825ng*hr/mL, greater than about 850 ng*hr/mL, greater than about 875ng*hr/mL, greater than about 900 ng*hr/mL, greater than about 925ng*hr/mL, greater than about 950 ng*hr/mL, greater than about 975ng*hr/mL, or greater than about 1000 ng*hr/mL after administration ofthe formulation to the patient. In some embodiments, formulationsadministered in the methods disclosed herein produce in a human subjectgroup an average AUC_((0-∞)) of cromolyn sodium of about 100 ng*hr/mL,about 110 ng*hr/mL, about 120 ng*hr/mL, about 130 ng*hr/mL, about 140ng*hr/mL, about 150 ng*hr/mL, about 160 ng*hr/mL, about 170 ng*hr/mL,about 180 ng*hr/mL, about 190 ng*hr/mL, about 200 ng*hr/mL, about 225ng*hr/mL, about 250 ng*hr/mL, about 275 ng*hr/mL, about 300 ng*hr/mL,about 325 ng*hr/mL, about 350 ng*hr/mL, about 375 ng*hr/mL, about 400ng*hr/mL, about 425 ng*hr/mL, about 450 ng*hr/mL, about 475 ng*hr/mL,about 500 ng*hr/mL, about 525 ng*hr/mL, about 550 ng*hr/mL, about 575ng*hr/mL, about 600 ng*hr/mL, about 625 ng*hr/mL, about 650 ng*hr/mL,about 675 ng*hr/mL, about 700 ng*hr/mL, about 725 ng*hr/mL, about 750ng*hr/mL, about 775 ng*hr/mL, about 800 ng*hr/mL, about 825 ng*hr/mL,about 850 ng*hr/mL, about 875 ng*hr/mL, about 900 ng*hr/mL, about 925ng*hr/mL, about 950 ng*hr/mL, about 975 ng*hr/mL, or about 1000 ng*hr/mLafter administration of the formulation to the patient.

In some embodiments, formulations administered in the methods disclosedherein produce in a human subject group an average C_(max) of a mastcell stabilizer greater than about 40 ng/mL, greater than about 50ng/mL, greater than about 60 ng/mL, greater than about 70 ng/mL, greaterthan about 80 ng/mL, greater than about 90 ng/mL, greater than about 100ng/mL, greater than about 110 ng/mL, greater than about 120 ng/mL,greater than about 130 ng/mL, greater than about 140 ng/mL, greater thanabout 150 ng/mL, greater than about 160 ng/mL, greater than about 170ng/mL, greater than about 180 ng/mL, greater than about 190 ng/mL,greater than about 200 ng/mL, greater than about 210 ng/mL, greater thanabout 220 ng/mL, greater than about 230 ng/mL, greater than about 240ng/mL, greater than about 250 ng/mL, greater than about 260 ng/mL,greater than about 270 ng/mL, greater than about 280 ng/mL, greater thanabout 290 ng/mL, greater than about 300 ng/mL, greater than about 310ng/mL, greater than about 320 ng/mL, greater than about 330 ng/mL,greater than about 340 ng/mL, greater than about 350 ng/mL, greater thanabout 360 ng/mL, greater than about 370 ng/mL, greater than about 380ng/mL, greater than about 390 ng/mL, or greater than about 400 ng/mLafter administration of the formulation to the patient. In someembodiments, formulations administered in the methods disclosed hereinproduce in a human subject group an average C_(max) of a mast cellstabilizer of about 50 mg/mL, about 60 ng/mL, about 70 ng/mL, about 80ng/mL, 90 ng/mL, about 100 ng/mL, about 110 ng/mL, about 120 ng/mL,about 130 ng/mL, about 140 ng/mL, about 150 ng/mL, about 160 ng/mL,about 170 ng/mL, about 180 ng/mL, about 190 ng/mL, about 200 ng/mL,about 210 ng/mL, about 220 ng/mL, about 230 ng/mL, about 240 ng/mL,about 250 ng/mL, 260 ng/mL, about 270 ng/mL, about 280 ng/mL, about 290ng/mL, about 300 ng/mL, about 310 ng/mL, about 320 ng/mL, about 330ng/mL, about 340 ng/mL, about 350 ng/mL, about 360 ng/mL, about 370ng/mL, about 380 ng/mL, about 390 ng/mL, or about 400 ng/mL afteradministration of the formulation to the patient.

In some embodiments, formulations administered in the methods disclosedherein produce in a human subject group an average C_(max) of cromolynsodium greater than about 40 ng/mL, greater than about 50 ng/mL, greaterthan about 60 ng/mL, greater than about 70 ng/mL, greater than about 80ng/mL, greater than about 90 ng/mL, greater than about 100 ng/mL,greater than about 110 ng/mL, greater than about 120 ng/mL, greater thanabout 130 ng/mL, greater than about 140 ng/mL, greater than about 150ng/mL, greater than about 160 ng/mL, greater than about 170 ng/mL,greater than about 180 ng/mL, greater than about 190 ng/mL, greater thanabout 200 ng/mL, greater than about 210 ng/mL, greater than about 220ng/mL, greater than about 230 ng/mL, greater than about 240 ng/mL,greater than about 250 ng/mL, greater than about 260 ng/mL, greater thanabout 270 ng/mL, greater than about 280 ng/mL, greater than about 290ng/mL, greater than about 300 ng/mL, greater than about 310 ng/mL,greater than about 320 ng/mL, greater than about 330 ng/mL, greater thanabout 340 ng/mL, greater than about 350 ng/mL, greater than about 360ng/mL, greater than about 370 ng/mL, greater than about 380 ng/mL,greater than about 390 ng/mL, or greater than about 400 ng/mL afteradministration of the formulation to the patient. In some embodiments,formulations administered in the methods disclosed herein produce in ahuman subject group an average C_(max) of cromolyn sodium of about 50mg/mL, about 60 ng/mL, about 70 ng/mL, about 80 ng/mL, 90 ng/mL, about100 ng/mL, about 110 ng/mL, about 120 ng/mL, about 130 ng/mL, about 140ng/mL, about 150 ng/mL, about 160 ng/mL, about 170 ng/mL, about 180ng/mL, about 190 ng/mL, about 200 ng/mL, about 210 ng/mL, about 220ng/mL, about 230 ng/mL, about 240 ng/mL, about 250 ng/mL, 260 ng/mL,about 270 ng/mL, about 280 ng/mL, about 290 ng/mL, about 300 ng/mL,about 310 ng/mL, about 320 ng/mL, about 330 ng/mL, about 340 ng/mL,about 350 ng/mL, about 360 ng/mL, about 370 ng/mL, about 380 ng/mL,about 390 ng/mL, or about 400 ng/mL after administration of theformulation to the patient.

Mast cell stabilizers may be administered to a subject in the methodsdisclosed herein by multiple administration routes, either alone orconcurrently, including but not limited to oral, oral inhalation,parenteral (e.g., intravenous, subcutaneous, intramuscular), implantssuch as osmotic pumps and depot implants, intranasal, buccal, topical,rectal, transdermal, vaginal, or sublingual administration routes. Insome embodiments of the methods disclosed herein, mast cell stabilizersmay be administered by a single route of administration. For example, incertain specific embodiments, the methods disclosed herein compriseadministration of a mast cell stabilizer, such as cromolyn sodium, withan inhalation device, e.g., a high efficiency nebulizer, withoutcoadministration of a mast cell stabilizer, e.g., cromolyn sodium, byanother route of administration, e.g., an oral solution.

Mast cell stabilizers may be formulated into any suitable dosage form,including but not limited to aerosols, aqueous oral dispersions, solidoral dosage forms, self-emulsifying dispersions, solid solutions,liposomal dispersions, pegylated liposomes, liquids, gels, implants,depots, syrups, elixirs, slurries, suspensions, lotions, gels, pastes,medicated sticks, balms, creams, ointments, aerosols, controlled releaseformulations, fast melt formulations, effervescent formulations,lyophilized formulations, tablets, powders, pills, dragees, capsules,delayed release formulations, extended release formulations, pulsatilerelease formulations, multiparticulate formulations, mixed immediaterelease formulations, controlled release formulations, enemas, rectalgels, rectal foams, rectal aerosols, vaginal gels, vaginal foams,vaginal aerosols, suppositories, jelly suppositories, or retentionenemas. Such formulations may be manufactured in a conventional manner,such as, by way of example only, conventional mixing, dissolving,granulating, dragee-making, levigating, emulsifying, encapsulating,entrapping or compression processes.

In some embodiments, the formulations disclosed herein may include oneor more inactive ingredients or pharmaceutical excipients that providesuitable properties of the formulation. Such inactive ingredients mayinclude one or more of the following classes.

“Albumin” refers to a family of globular proteins, the most common ofwhich is serum albumin. Albumins are commonly found in blood plasma andfunction to regulate colloidal osmotic pressure of the blood. Albuminproteins found in the plasma bind some pharmaceutical compounds to formcomplexes. Complexation of albumin with pharmaceutical compounds, e.g.,mast cell stabilizers, can influence the pharmaceutical compounds'plasma half-life and/or biological half-life in the body by preventingmetabolism and/or excretion of the complexed compounds. In someembodiments, compositions disclosed herein include albumin and a mastcell stabilizer, e.g., cromolyn sodium.

“Antifoaming agents” reduce foaming during processing which can resultin coagulation of aqueous dispersions, bubbles in the finished film, orgenerally impair processing. Exemplary anti-foaming agents includesilicon emulsions or sorbitan sesquoleate.

“Antioxidants” include, for example, butylated hydroxytoluene (BHT),sodium ascorbate, ascorbic acid, sodium metabisulfite and tocopherol. Incertain embodiments, antioxidants enhance chemical stability whererequired.

“Binders” impart cohesive qualities and include, e.g., alginic acid andsalts thereof; cellulose derivatives such as carboxymethylcellulose,methylcellulose (e.g., Methocel®), hydroxypropylmethylcellulose,hydroxyethylcellulose, hydroxypropylcellulose (e.g., Klucel®),ethylcellulose (e.g., Ethocel®), and microcrystalline cellulose (e.g.,Avicel®); microcrystalline dextrose; amylose; magnesium aluminumsilicate; polysaccharide acids; bentonites; gelatin;polyvinylpyrrolidone/vinyl acetate copolymer; crosspovidone; povidone;starch; pregelatinized starch; tragacanth, dextrin, a sugar, such assucrose (e.g., Dipac®), glucose, dextrose, molasses, mannitol, sorbitol,xylitol (e.g., Xylitab®), and lactose; a natural or synthetic gum suchas acacia, tragacanth, ghatti gum, mucilage of isapol husks,polyvinylpyrrolidone (e.g., Polyvidone® CL, Kollidon® CL, Polyplasdone®XL-10), larch arabogalactan, Veegum®, polyethylene glycol, waxes, sodiumalginate, and the like.

“Carriers” or “carrier materials” include any commonly used excipientsin pharmaceutics and should be selected on the basis of compatibilitywith the specific mast cell stabilizer and the release profileproperties of the desired dosage form. Exemplary carrier materialsinclude, e.g., binders, suspending agents, disintegration agents,filling agents, surfactants, solubilizers, stabilizers, lubricants,wetting agents, diluents, and the like. “Pharmaceutically compatiblecarrier materials” may include, but are not limited to, acacia, gelatin,colloidal silicon dioxide, calcium glycerophosphate, calcium lactate,maltodextrin, glycerine, magnesium silicate, polyvinylpyrollidone (PVP),cholesterol, cholesterol esters, sodium caseinate, soy lecithin,taurocholic acid, phosphotidylcholine, sodium chloride, tricalciumphosphate, dipotassium phosphate, cellulose and cellulose conjugates,sugars sodium stearoyl lactylate, carrageenan, monoglyceride,diglyceride, pregelatinized starch, and the like. See, e.g., Remington:The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: MackPublishing Company, 1995); Hoover, John E., Remington's PharmaceuticalSciences, Mack Publishing Co., Easton, Pa. 1975; Liberman, H. A. andLachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York,N.Y., 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems,Seventh Ed. (Lippincott Williams & Wilkins 1999).

“Dispersing agents” and/or “viscosity modulating agents” includematerials that control the diffusion and homogeneity of a drug throughliquid media or a granulation method or blend method. In someembodiments, these agents also facilitate the effectiveness of a coatingor eroding matrix. Exemplary diffusion facilitators/dispersing agentsinclude, e.g., hydrophilic polymers, electrolytes, Tween® 60 or 80, PEG,Tyloxapol, polyvinylpyrrolidone (PVP; commercially known as Plasdone®),and the carbohydrate-based dispersing agents such as, for example,hydroxypropyl celluloses (e.g., HPC, HPC-SL, and HPC-L), hydroxypropylmethylcelluloses (e.g., HPMC K100, HPMC K4M, HPMC K15M, and HPMC K100M),carboxymethylcellulose sodium, methylcellulose, hydroxyethylcellulose,hydroxypropylcellulose, hydroxypropylmethylcellulose phthalate,hydroxypropylmethylcellulose acetate stearate (HPMCAS), noncrystallinecellulose, magnesium aluminum silicate, triethanolamine, polyvinylalcohol (PVA), vinyl pyrrolidone/vinyl acetate copolymer (S630),4-(1,1,3,3-tetramethylbutyl)-phenol polymer with ethylene oxide andformaldehyde (also known as tyloxapol), poloxamers (e.g., PluronicsF68®, F88®, and F108®, which are block copolymers of ethylene oxide andpropylene oxide); and poloxamines (e.g., Tetronic 908®, also known asPoloxamine 908®, which is a tetrafunctional block copolymer derived fromsequential addition of propylene oxide and ethylene oxide toethylenediamine (BASF Corporation, Parsippany, N.J.)),polyvinylpyrrolidone K12, polyvinylpyrrolidone K17, polyvinylpyrrolidoneK25, or polyvinylpyrrolidone K30, polyvinylpyrrolidone/vinyl acetatecopolymer (S-630), polyethylene glycol, e.g., the polyethylene glycolcan have a molecular weight of about 300 to about 6000, or about 3350 toabout 4000, or about 7000 to about 5400, sodium carboxymethylcellulose,methylcellulose, polysorbate-80, sodium alginate, gums, such as, e.g.,gum tragacanth and gum acacia, guar gum, xanthans, including xanthangum, sugars, cellulosics, such as, e.g., sodium carboxymethylcellulose,methylcellulose, sodium carboxymethylcellulose, polysorbate-80, sodiumalginate, polyethoxylated sorbitan monolaurate, polyethoxylated sorbitanmonolaurate, povidone, carbomers, polyvinyl alcohol (PVA), alginates,chitosans and combinations thereof. Plasticizcers such as cellulose ortriethyl cellulose can also be used as dispersing agents. Dispersingagents particularly useful in liposomal dispersions and self-emulsifyingdispersions are dimyristoyl phosphatidyl choline, natural phosphatidylcholine from eggs, natural phosphatidyl glycerol from eggs, cholesteroland isopropyl myristate.

“Diluent” refers to chemical compounds that are used to dilute thecompound of interest prior to delivery. Diluents can also be used tostabilize compounds because they can provide a more stable environment.Salts dissolved in buffered solutions, including, but not limited to, aphosphate buffered saline solution, are utilized as diluents in the art,and can also provide pH control or maintenance. In certain embodiments,diluents increase bulk of the composition to facilitate compression orcreate sufficient bulk for homogenous blend for capsule filling. Suchcompounds include e.g., lactose, starch, mannitol, sorbitol, dextrose,microcrystalline cellulose such as Avicel®; dibasic calcium phosphate,dicalcium phosphate dihydrate; tricalcium phosphate, calcium phosphate;anhydrous lactose, spray-dried lactose; pregelatinized starch,compressible sugar, such as Di-Pac® (Amstar); mannitol,hydroxypropylmethylcellulose, hydroxypropylmethylcellulose acetatestearate, sucrose-based diluents, confectioner's sugar; monobasiccalcium sulfate monohydrate, calcium sulfate dihydrate; calcium lactatetrihydrate, dextrates; hydrolyzed cereal solids, amylose; powderedcellulose, calcium carbonate; glycine, kaolin; mannitol, sodiumchloride; inositol, bentonite, and the like.

The term “disintegrate” includes both the dissolution and dispersion ofthe dosage form when contacted with gastrointestinal fluid.“Disintegration agents” or “disintegrants” facilitate the breakup ordisintegration of a substance. Examples of disintegration agents includea starch, e.g., a natural starch such as corn starch or potato starch, apregelatinized starch such as National 1551 or Amijel®, or sodium starchglycolate such as Promogel® or Explotab®, a cellulose such as a woodproduct, methylcrystalline cellulose, e.g., Avicel®, Avicel® PH101,Avicel® PH102, Avicel® PH105, Elcema® P100, Emcocel®, Vivacel®, MingTia®, and Solka-Floc®, methylcellulose, croscarmellose, or across-linked cellulose, such as cross-linked sodiumcarboxymethylcellulose (Ac-Di-Sol®), cross-linkedcarboxymethylcellulose, or cross-linked croscarmellose, a cross-linkedstarch such as sodium starch glycolate, a cross-linked polymer such ascrosspovidone, a cross-linked polyvinylpyrrolidone, alginate such asalginic acid or a salt of alginic acid such as sodium alginate, a claysuch as Veegum® HV (magnesium aluminum silicate), a gum such as agar,guar, locust bean, Karaya, pectin, or tragacanth, sodium starchglycolate, bentonite, a natural sponge, a surfactant, a resin such as acation-exchange resin, citrus pulp, sodium lauryl sulfate, sodium laurylsulfate in combination starch, and the like.

An “enteric coating” is a substance that remains substantially intact inthe stomach but dissolves and releases the drug in the small intestineor colon. Generally, the enteric coating comprises a polymeric materialthat prevents release in the low pH environment of the stomach but thationizes at a higher pH, typically a pH of 6 to 7, and thus dissolvessufficiently in the small intestine or colon to release the active agenttherein.

“Erosion facilitators” include materials that control the erosion of aparticular material in gastrointestinal fluid. Erosion facilitators aregenerally known to those of ordinary skill in the art. Exemplary erosionfacilitators include, e.g., hydrophilic polymers, electrolytes,proteins, peptides, and amino acids. Combinations of one or more erosionfacilitator with one or more diffusion facilitator can also be used inthe present compositions.

“Filling agents” include compounds such as lactose, calcium carbonate,calcium phosphate, dibasic calcium phosphate, calcium sulfate,microcrystalline cellulose, cellulose powder, dextrose, dextrates,dextran, starches, pregelatinized starch, sucrose, xylitol, lactitol,mannitol, sorbitol, sodium chloride, polyethylene glycol, and the like.

“Flavoring agents” and/or “sweeteners” useful in the formulationsdescribed herein, include, e.g., acacia syrup, acesulfame K, alitame,anise, apple, aspartame, banana, Bavarian cream, berry, black currant,butterscotch, calcium citrate, camphor, caramel, cherry, cherry cream,chocolate, cinnamon, bubble gum, citrus, citrus punch, citrus cream,cotton candy, cocoa, cola, cool cherry, cool citrus, cyclamate,cylamate, dentomint, dextrose, eucalyptus, eugenol, fructose, fruitpunch, ginger, glycyrrhetinate, glycyrrhiza (licorice) syrup, grape,grapefruit, honey, isomalt, lemon, lime, lemon cream, monoammoniumglyrrhizinate (MagnaSweet®), maltol, mannitol, maple, marshmallow,menthol, mint cream, mixed berry, neohesperidine DC, neotame, orange,pear, peach, peppermint, peppermint cream, Prosweet® Powder, raspberry,root beer, rum, saccharin, safrole, sorbitol, spearmint, spearmintcream, strawberry, strawberry cream, stevia, sucralose, sucrose, sodiumsaccharin, saccharin, aspartame, acesulfame potassium, mannitol, talin,sylitol, sucralose, sorbitol, Swiss cream, tagatose, tangerine,thaumatin, tutti fruitti, vanilla, walnut, watermelon, wild cherry,wintergreen, xylitol, or any combination of these flavoring ingredients,e.g., anise-menthol, cherry-anise, cinnamon-orange, cherry-cinnamon,chocolate-mint, honey-lemon, lemon-lime, lemon-mint, menthol-eucalyptus,orange-cream, vanilla-mint, and mixtures thereof.

“Lubricants” and “glidants” are compounds that prevent, reduce orinhibit adhesion or friction of materials. Exemplary lubricants include,e.g., stearic acid, calcium hydroxide, talc, sodium stearyl fumerate, ahydrocarbon such as mineral oil, or hydrogenated vegetable oil such ashydrogenated soybean oil (Sterotex®), higher fatty acids and theiralkali-metal and alkaline earth metal salts, such as aluminum, calcium,magnesium, zinc, stearic acid, sodium stearates, glycerol, talc, waxes,Stearowet®, boric acid, sodium benzoate, sodium acetate, sodiumchloride, leucine, a polyethylene glycol (e.g., PEG-4000) or amethoxypolyethylene glycol such as Carbowax™ sodium oleate, sodiumbenzoate, glyceryl behenate, polyethylene glycol, magnesium or sodiumlauryl sulfate, colloidal silica such as Syloid™, Cab-O-Sil®, a starchsuch as corn starch, silicone oil, a surfactant, and the like.

“Plasticizers” are compounds used to soften the microencapsulationmaterial or film coatings to make them less brittle. Suitableplasticizers include, e.g., polyethylene glycols such as PEG 300, PEG400, PEG 600, PEG 1450, PEG 3350, and PEG 800, stearic acid, propyleneglycol, oleic acid, triethyl cellulose and triacetin. In someembodiments, plasticizers can also function as dispersing agents orwetting agents.

In certain embodiments, compositions provided herein may also includeone or more preservatives to inhibit microbial activity. Suitablepreservatives include mercury-containing substances such as merfen andthiomersal; stabilized chlorine dioxide; octinidine; and quaternaryammonium compounds such as benzalkonium chloride, cetyltrimethylammoniumbromide and cetylpyridinium chloride.

“Solubilizers” include compounds such as triacetin, triethylcitrate,ethyl oleate, ethyl caprylate, sodium lauryl sulfate, sodium doccusate,vitamin E TPGS, polysorbates (Tweens) dimethylacetamide,N-methylpyrrolidone, N-hydroxyethylpyrrolidone, polyvinylpyrrolidone,hydroxypropylmethyl cellulose, hydroxypropyl cyclodextrins, ethanol,n-butanol, isopropyl alcohol, cholesterol, bile salts, polyethyleneglycol 200-600, glycofurol, transcutol, propylene glycol, and dimethylisosorbide and the like.

“Stabilizers” include compounds such as any antioxidation agents, e.g.,citric acid, EDTA and pharmaceutically acceptable salts thereof,buffers, acids, preservatives and the like.

“Suspending agents” include compounds such as polyvinylpyrrolidone,e.g., polyvinylpyrrolidone K12, polyvinylpyrrolidone K17,polyvinylpyrrolidone K25, or polyvinylpyrrolidone K30, vinylpyrrolidone/vinyl acetate copolymer (S630), polyethylene glycol, e.g.,the polyethylene glycol can have a molecular weight of about 300 toabout 6000, or about 3350 to about 4000, or about 7000 to about 5400,sodium carboxymethylcellulose, methylcellulose,hydroxypropylmethylcellulose, hydroxymethylcellulose acetate stearate,polysorbate-80, hydroxyethylcellulose, sodium alginate, gums, such as,e.g., gum tragacanth and gum acacia, guar gum, xanthans, includingxanthan gum, sugars, cellulosics, such as, e.g., sodiumcarboxymethylcellulose, methylcellulose, sodium carboxymethylcellulose,hydroxypropylmethylcellulose, hydroxyethylcellulose, polysorbate-80,sodium alginate, polyethoxylated sorbitan monolaurate, polyethoxylatedsorbitan monolaurate, povidone and the like.

“Surfactants” include compounds such as sodium lauryl sulfate, sodiumdocusate, Tween 60 or 80, triacetin, vitamin E TPGS, sorbitanmonooleate, polyoxyethylene sorbitan monooleate, polysorbates,polaxomers, bile salts, glyceryl monostearate, copolymers of ethyleneoxide and propylene oxide, e.g., Pluronic® (BASF), and the like. Someother surfactants include polyoxyethylene fatty acid glycerides andvegetable oils, e.g., polyoxyethylene (60) hydrogenated castor oil; andpolyoxyethylene alkylethers and alkylphenyl ethers, e.g., octoxynol 10,octoxynol 40. In some embodiments, surfactants may be included toenhance physical stability or for other purposes.

“Viscosity enhancing agents” include, e.g., methyl cellulose, xanthangum, carboxymethyl cellulose, hydroxypropyl cellulose,hydroxypropylmethyl cellulose, hydroxypropylmethyl cellulose acetatestearate, hydroxypropylmethyl cellulose phthalate, carbomer, polyvinylalcohol, alginates, acacia, chitosans, and combinations thereof.

“Wetting agents” include compounds such as oleic acid, glycerylmonostearate, sorbitan monooleate, sorbitan monolaurate, triethanolamineoleate, polyoxyethylene sorbitan monooleate, polyoxyethylene sorbitanmonolaurate, sodium docusate, sodium oleate, sodium lauryl sulfate,sodium doccusate, triacetin, Tween 80, vitamin E TPGS, ammonium saltsand the like.

It should be appreciated that there is considerable overlap betweenclasses of inactive ingredients. Thus, the above-listed ingredientsshould be taken as merely exemplary, and not limiting, of the types ofinactive ingredients that can be included in formulations describedherein. The amounts of such inactive ingredients can be readilydetermined by one skilled in the art, according to the particularproperties desired.

In certain specific embodiments, formulations for administration of mastcell stabilizers in the methods disclosed herein include, but are notlimited to, Aararre, Acecromol, Acromax, Acticrom, Aeropaxyn, Alercom,Alercrom, Alercrom Nasal, Alerg, Alerg AT, Alerg Nasenspray, Alergocrom,Alerion, Allercrom, Allerg-Abak, Allergo-COMOD, Allergocomod,Allergocrom, Allergocrom Kombi, Allergocrom Kombinationspackung,Allergojovis, Allergostop, Allergotin, Allergoval, Allersol, Alloptrex,Apo-Cromolyn, Botastin, Brol-Eze, Chromosol Ophta, Clariteyes, ClaritynAllergy Eyedrops, Clarityn Eye Drops, Claroftal, Clo-5, Coldacrom,Colimune, Croglina, Crolidin, Crolom, Crom-Ophtal, Crom-OphtalKombipackung, Crom-Ophtal Sine, Cromabak, Cromadoses, Cromal, Cromantal,Cromedil, Cromedil Unidose, Cromese, Cromex, Cromo, Cromo Asma, CromoEDP, Cromo Einzeldosis, Cromo Kombipackung, Cromo UD, Cromo-Comod,Cromo-Pos, Cromo-Spray, Cromobene, Cromocato, Cromodyn, Cromoftal,Cromogen, Cromoglicin, Cromohexal, Cromohexal Kombipackung, CromohexalUD, Cromol, Cromolerg, Cromolergin UD, Cromolind, Cromolux, Cromophtal,Cromopp, Cromoptic, Cromoptic Unidose, Cromorhinol, Cromosan, Cromosoft,Cromosol, Cromosol UD, Cromovet, Cromunal, Cronacol, Cronase, Cropoz,Cropoz G, Cropoz N, Crorin, Cusicrom, Cusilyn, Diffusyl, Dilospir,Dispacromil, Dispacromil Sine, DNCG, DNCG PPS, Duobetic, Duracroman,Erystamine-K, Esirhinol, Exaler, Farmacrom, Fenistil Eye Drops, Fenolip,Fintal, Fivent, Flenid, Flui-DNCG, Fluvet, Frenal, Gaster, Gastrocrom,Gastrofrenal, Gelodrin, Gen-Cromoglycate, Gen-Cromoglycate Sterinebs,Gen-Cromolyn, Glicacil, Glicinal, Glinor, Hay-Crom, Hayfever Eye Drops,Hexacroman, Humex Conjonctivite Allergique, Ifiral, Indoprex, Inostral,Intal, Intal 5, Intal Forte, Intal N, Intal Nasal, Intal Nebulizador,Intal Nebulizer, Intal Spincaps, Intal Syncroner, Intercron, Introl,Iopanchol, Kaosyl, Kiddicrom, Klonalcrom, Lecrolyn, LogomedHeuschnupfen-Spray, Lomudal, Lomudal Nebuliser, Lomudal sans FCKW,Lomudas, Lomupren, Lomusol, Lomuspray, Maxicrom, Multicrom, MulticromUnidose, Nalcrom, Nalcron, Nasalcrom, Nasivin gegen Heuschnupfen,Nasmil, Natriumcromoglicaat, Nebulasma, Nebulcrom, NovacroNovo-Cromolyn, Novo-Cromolyn Nebulizer, Nu-Cromolyn Plast Ophtacalm,Ophtacalm Unidose, Opticrom, Opticrom Allergy, Opticrom Aqueous,Opticrom UD, Opticron, Opticron Unidose, Optrex Hayfever Allergy,Oralcrom, Otriven H, Otrivin Hooikoorts, Padiacrom, Pentacrom, Pentatop,PMS-Sodium Cromoglycate, Poledin, Pollenase Allergy, Pollyferm,Prevalin, Primover, Prothanon Cromo, Pulbil, Pulmosin, Renocil, ResistonTwo, Rhinaris-CS Anti-Allergic Nasal Mist, Rilan, Rinil, Rinilyn,Rinofrenal, Rynacrom, Rynacrom M, Sificrom, Sofro, Solu-Crom, Spaziron,Spralyn, Stadaglicin, Steri-Neb Cromogen, Stop-Allerg, Taleum,Ufocollyre, Vekfanol, Vicrom, Vistacrom, Vivicrom, Vividrin, Vividriniso EDO, Viz-On, Zineli, or Zulboral.

Solid Oral Formulations

In some embodiments, the solid dosage forms disclosed herein may be inthe form of a tablet, (including a suspension tablet, a fast-melttablet, a bite-disintegration tablet, a rapid-disintegration tablet, aneffervescent tablet, an osmotic pump tablet, or a caplet), a pill, apowder (including a sterile packaged powder, a dispensable powder, or aneffervescent powder), a capsule (including both soft or hard capsules,e.g., capsules made from animal-derived gelatin or plant-derived HPMC,or “sprinkle capsules”), solid dispersion, solid solution, bioerodibledosage form, controlled release formulations, pulsatile release dosageforms, multiparticulate dosage forms, pellets, or granules. In someembodiments, systemically effective amounts of mast cell stabilizers areachieved with solid oral formulations by including one or more ofpermeation enhancers and enteric coatings in the solid oralformulations. In some embodiments, enteric coatings regulate thedelivery a mast cell stabilizer during its passage through the stomachand intestine.

The pharmaceutical solid dosage forms described herein can include amast cell stabilizer and one or more pharmaceutically inactiveingredients such as a compatible carrier, binder, filling agent,suspending agent, flavoring agent, sweetening agent, disintegratingagent, dispersing agent, surfactant, lubricant, colorant, diluent,solubilizer, moistening agent, plasticizer, stabilizer, penetrationenhancer, wetting agent, anti-foaming agent, antioxidant, preservative,or one or more combination thereof.

In some embodiments, solid dosage forms, e.g., tablets, effervescenttablets, and capsules, are prepared by mixing particles of a mast cellstabilizer with one or more pharmaceutical excipients to form a bulkblend composition. When referring to these bulk blend compositions ashomogeneous, it is meant that the particles of the mast cell stabilizerare dispersed evenly throughout the composition so that the compositionmay be readily subdivided into equally effective unit dosage forms, suchas tablets, pills, and capsules. The individual unit dosages may alsoinclude film coatings, which disintegrate upon oral ingestion or uponcontact with diluent. These formulations can be manufactured byconventional pharmacological techniques, e.g., one or a combination of:(1) dry mixing, (2) direct compression, (3) milling, (4) dry ornon-aqueous granulation, (5) wet granulation, and (6) fusion. See, e.g.,Lachman et al., The Theory and Practice of Industrial Pharmacy (1986).Other methods include, e.g., spray drying, pan coating, meltgranulation, granulation, fluidized bed spray drying or coating (e.g.,wurster coating), tangential coating, top spraying, tableting, extrudingand the like.

Pharmaceutical preparations for oral use can be obtained by mixing oneor more solid excipient with one or more mast cell stabilizers,optionally grinding the resulting mixture, and processing the mixture ofgranules, after adding suitable auxiliaries, if desired, to obtaintablets or dragee cores. In some embodiments, dragee cores are providedwith suitable coatings. For this purpose, concentrated sugar solutionsmay be used, which may optionally contain gum arabic, talc,polyvinylpyrrolidone, carbopol gel, polyethylene glycol, and/or titaniumdioxide, lacquer solutions, and suitable organic solvents or solventmixtures. Dyestuffs or pigments may be added to the tablets or drageecoatings for identification or to characterize different combinations ofactive compound doses.

In other embodiments, a powder including a mast cell stabilizer may beformulated to include one or more pharmaceutical excipients and flavors.Such a powder may be prepared, for example, by mixing the formulationand optional pharmaceutical excipients to form a bulk blend composition.Additional embodiments also include a suspending agent and/or a wettingagent. This bulk blend is uniformly subdivided into unit dosagepackaging or multi-dosage packaging units.

Compressed tablets are solid dosage forms prepared by compacting thebulk blend of the formulations described above. In some embodiments, thecompressed tablets will include a film surrounding the final compressedtablet. In some embodiments, the film coating can provide a delayedrelease of the mast cell stabilizer from the formulation. In otherembodiments, the film coating aids in patient compliance. Film coatingssuch as Opadry® typically range from about 1% to about 3% of the tabletweight. In other embodiments, the compressed tablets include one or morepharmaceutical excipients.

A capsule may be prepared, for example, by placing the bulk blend of theformulation of the mast cell stabilizer inside of a capsule. In someembodiments, the formulations (non-aqueous suspensions and solutions)are placed in a soft gelatin capsule. In other embodiments, theformulations are placed in standard gelatin capsules or non-gelatincapsules such as capsules comprising HPMC. In other embodiments, theformulation is placed in a sprinkle capsule, wherein the capsule may beswallowed whole or the capsule may be opened and the contents sprinkledon food prior to eating. In some embodiments, the therapeutic dose issplit into multiple (e.g., two, three, or four) capsules. In someembodiments, the entire dose of the formulation is delivered in acapsule form.

In some embodiments, dosage forms may include microencapsulatedformulations. Materials useful for the microencapsulation includematerials compatible with mast cell stabilizers, which sufficientlyisolate mast cell stabilizers from other non-compatible excipients.Materials compatible with mast cell stabilizers are those that delay therelease of the mast cell stabilizers in vivo. Exemplarymicroencapsulation materials useful for delaying the release of theformulations include, but are not limited to, hydroxypropyl celluloseethers (HPC) such as Klucel® or Nisso HPC, low-substituted hydroxypropylcellulose ethers (L-HPC), hydroxypropyl methyl cellulose ethers (HPMC)such as Seppifilm-LC, Pharmacoat®, Metolose SR, Methocel®-E, Opadry YS,PrimaFlo, Benecel MP824, and Benecel MP843, methylcellulose polymerssuch as Methocel®-A, hydroxypropylmethylcellulose acetate stearate Aqoat(HF-LS, HF-LG, HF-MS) and Metolose®, Ethylcelluloses (EC) and mixturesthereof such as E461, Ethocel®, Aqualon®-EC, Surelease®, Polyvinylalcohol (PVA) such as Opadry AMB, hydroxyethylcelluloses such asNatrosol®, carboxymethylcelluloses and salts of carboxymethylcelluloses(CMC) such as Aqualon®-CMC, polyvinyl alcohol and polyethylene glycolco-polymers such as Kollicoat IR®, monoglycerides (Myverol),triglycerides (KLX), polyethylene glycols, modified food starch, acrylicpolymers and mixtures of acrylic polymers with cellulose ethers such asEudragit® EPO, Eudragit® L30D-55, Eudragit® FS 30D Eudragit® L100-55,Eudragit® L100, Eudragit® S100, Eudragit® RD100, Eudragit® E100,Eudragit® L12.5, Eudragit® S12.5, Eudragit® NE30D, and Eudragit® NE 40D,cellulose acetate phthalate, sepifilms such as mixtures of HPMC andstearic acid, cyclodextrins, and mixtures of these materials. In someembodiments, plasticizers such as polyethylene glycols, e.g., PEG 300,PEG 400, PEG 600, PEG 1450, PEG 3350, and PEG 800, stearic acid,propylene glycol, oleic acid, and triacetin are incorporated into themicroencapsulation material.

Microencapsulated mast cell stabilizers may be formulated by methodsknown by one of ordinary skill in the art. Such known methods include,e.g., spray drying processes, spinning disk-solvent processes, hot meltprocesses, spray chilling methods, fluidized bed, electrostaticdeposition, centrifugal extrusion, rotational suspension separation,polymerization at liquid-gas or solid-gas interface, pressure extrusion,or spraying solvent extraction bath. In addition to these, severalchemical techniques, e.g., complex coacervation, solvent evaporation,polymer-polymer incompatibility, interfacial polymerization in liquidmedia, in situ polymerization, in-liquid drying, and desolvation inliquid media could also be used. Furthermore, other methods such asroller compaction, extrusion/spheronization, coacervation, ornanoparticle coating may also be used.

In other embodiments, the formulations described herein are soliddispersions. Methods of producing such solid dispersions are known inthe art and include, but are not limited to, for example, U.S. Pat. Nos.4,343,789, 5,340,591, 5,456,923, 5,700,485, 5,723,269, and U.S. Pub.Appl 2004/0013734, each of which is specifically incorporated byreference. In still other embodiments, the formulations described hereinare solid solutions. Solid solutions incorporate a substance togetherwith the mast cell stabilizer and other excipients such that heating themixture results in dissolution of the drug and the resulting compositionis then cooled to provide a solid blend which can be further formulatedor directly added to a capsule or compressed into a tablet. Methods ofproducing such solid solutions are known in the art and include, but arenot limited to, for example, U.S. Pat. Nos. 4,151,273, 5,281,420, and6,083,518, each of which is specifically incorporated by reference.

In other embodiments, formulations described herein include a matrixbased dosage form. In a matrix-based dosage form described herein, atleast one mast cell stabilizer and optional pharmaceutically acceptableexcipient(s) are dispersed within a polymeric matrix, which typicallycomprises one or more water-soluble polymers and/or one or morewater-insoluble polymers. The drug can be released from the dosage formby diffusion and/or erosion. Suitable water-soluble polymers include,but are not limited to, polyvinyl alcohol, polyvinylpyrrolidone,methylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose,or polyethylene glycol, and/or mixtures thereof. Suitablewater-insoluble polymers also include, but are not limited to,ethylcellulose, cellulose acetate, cellulose propionate, celluloseacetate propionate, cellulose acetate butyrate, cellulose acetatephthalate, cellulose triacetate, poly (methyl methacrylate), poly (ethylmethacrylate), poly (butyl methacrylate), poly (isobutyl methacrylate),and poly (hexyl methacrylate), poly (isodecyl methacrylate), poly(lauryl methacrylate), poly (phenyl methacrylate), poly (methylacrylate), poly (isopropyl acrylate), poly (isobutyl acrylate), poly(octadecyl acrylate), poly (ethylene), poly (ethylene) low density, poly(ethylene) high density, poly (ethylene oxide), poly (ethyleneterephthalate), poly (vinyl isobutyl ether), poly (vinyl acetate), poly(vinyl chloride) or polyurethane, an d/or mixtures thereof. Suitablepharmaceutically acceptable excipients include, but are not limited to,carriers, such as sodium citrate and dicalcium phosphate; fillers orextenders, such as stearates, silicas, gypsum, starches, lactose,sucrose, glucose, mannitol, talc, and silicic acid; binders, such ashydroxypropyl methylcellulose, hydroxymethyl-cellulose, alginates,gelatin, polyvinyl pyrrolidone, sucrose, and acacia; humectants, such asglycerol; disintegrating agents, such as agar, calcium carbonate, potatoand tapioca starch, alginic acid, certain silicates, EXPLOTAB,crospovidone, and sodium carbonate; solution retarding agents, such asparaffin; absorption accelerators, such as quaternary ammoniumcompounds; wetting agents, such as cetyl alcohol and glycerolmonostearate; absorbents, such as kaolin and bentonite clay; lubricants,such as talc, calcium stearate, magnesium stearate, solid polyethyleneglycols, and sodium lauryl sulfate; stabilizers, such as fumaric acid;coloring agents; buffering agents; dispersing agents; preservatives;organic acids; and organic bases. The aforementioned excipients aregiven as examples only and are not meant to include all possiblechoices. Additionally, many excipients can have more than one role orfunction, or can be classified in more than one group; theclassifications are descriptive only, and are not intended to limit anyuse of a particular excipient.

Matrix formulations of the present invention can be prepared by using,for example, direct compression or wet granulation. A functional coatingcan then be applied. Additionally, a barrier or sealant coat can beapplied over a matrix tablet core prior to application of a functionalcoating. The barrier or sealant coat can serve the purpose of separatingan active ingredient from a functional coating, which can interact withthe active ingredient, or it can prevent moisture from contacting theactive ingredient.

In some embodiments, the modified-release formulations described hereinare provided as osmotic pump dosage forms. In an osmotic pump dosageform, a core containing at least one mast cell stabilizer and optionallyat least one osmotic excipient is typically encased by a selectivelypermeable membrane having at least one orifice. The selectivelypermeable membrane is generally permeable to water, but impermeable tothe drug. When the system is exposed to body fluids, water penetratesthrough the selectively permeable membrane into the core containing thedrug and optional osmotic excipients. The osmotic pressure increaseswithin the dosage form. Consequently, the drug is released through theorifice(s) in an attempt to equalize the osmotic pressure across theselectively permeable membrane.

In more complex pumps, the dosage form can contain two internalcompartments in the core. The first compartment contains the drug andthe second compartment can contain a polymer, which swells on contactwith aqueous fluid. After ingestion, this polymer swells into thedrug-containing compartment, diminishing the volume occupied by thedrug, thereby forcing the drug from the device at a controlled rate overan extended period of time. Such dosage forms are often used when a zeroorder release profile is desired. Suitable swellable polymers typicallyinteract with water and/or aqueous biological fluids, which causes themto swell or expand to an equilibrium state. Acceptable polymers exhibitthe ability to swell in water and/or aqueous biological fluids,retaining a significant portion of such imbibed fluids within theirpolymeric structure, so as to increase the hydrostatic pressure withinthe dosage form. The polymers can swell or expand to a very high degree,usually exhibiting a 2- to 50-fold volume increase. The polymers can benon-cross-linked or cross-linked. In some embodiments, the swellablepolymers are hydrophilic polymers.

In some embodiments, mast cell stabilizers can be provided in amultiparticulate membrane-modified formulation. Membrane-modifiedformulations can be made by preparing a rapid release core, which can bea monolithic (e.g., tablet) or multi-unit (e.g., pellet) type, andcoating the core with a membrane. The membrane-modified core can then befurther coated with a functional coating. In between themembrane-modified core and functional coating, a barrier or sealant canbe applied. The mast cell stabilizer can be formed into an active coreby applying the compound to a nonpareil seed. The at least one mast cellstabilizer can be applied with or without additional excipients onto theinert cores, and can be sprayed from solution or suspension using afluidized bed coater (e.g., Wurster coating) or pan coating system.Alternatively, a mast cell stabilizer can be applied as a powder ontothe inert cores using a binder to bind the mast cell stabilizer onto thecores. Active cores can also be formed by extrusion of the core withsuitable plasticizers and any other processing aids as necessary.

The pharmaceutical solid oral dosage forms described herein can befurther formulated to provide a controlled release of the mast cellstabilizer. Controlled release refers to the release of the mast cellstabilizer from a dosage form in which it is incorporated according to adesired profile over an extended period of time. Controlled releaseprofiles include, for example, sustained release, prolonged release,pulsatile release, and delayed release profiles. In contrast toimmediate release compositions, controlled release compositions allowdelivery of an agent to a subject over an extended period of timeaccording to a predetermined profile. Such release rates can providetherapeutically effective levels of agent for an extended period of timeand thereby provide a longer period of pharmacologic response whileminimizing side effects as compared to conventional rapid release dosageforms. Such longer periods of response provide for many benefits thatare not achieved with the corresponding short acting, immediate releasepreparations.

In some embodiments, the solid dosage forms described herein can beformulated as enteric coated delayed release oral dosage forms, i.e., asan oral dosage form of a pharmaceutical composition as described hereinwhich utilizes an enteric coating to affect release in the smallintestine of the gastrointestinal tract. The enteric coated dosage formmay be a compressed or molded or extruded tablet/mold (coated oruncoated) containing granules, powder, pellets, beads or particles ofthe active ingredient and/or other composition components, which arethemselves coated or uncoated. The enteric coated oral dosage form mayalso be a capsule (coated or uncoated) containing pellets, beads orgranules of the solid carrier or the composition, which are themselvescoated or uncoated.

The term “delayed release” as used herein refers to the delivery so thatthe release can be accomplished at some generally predictable locationin the intestinal tract more distal to that which would have beenaccomplished if there had been no delayed release alterations. In someembodiments the method for delay of release is coating. Any coatingsshould be applied to a sufficient thickness such that the entire coatingdoes not dissolve in the gastrointestinal fluids at pH below about 5,but does dissolve at pH about 5 and above. It is expected that anyanionic polymer exhibiting a pH-dependent solubility profile can be usedas an enteric coating in the methods and compositions described hereinto achieve delivery to the lower gastrointestinal tract. In someembodiments the polymers described herein are anionic carboxylicpolymers. In other embodiments, the polymers and compatible mixturesthereof, and some of their properties, include, but are not limited toshellac acrylic polymers, cellulose derivatives, and poly vinyl acetatephthalate (PVAP).

Conventional coating techniques such as spray or pan coating areemployed to apply coatings. The coating thickness must be sufficient toensure that the oral dosage form remains intact until the desired siteof topical delivery in the intestinal tract is reached.

Liquid Oral Formulations

Liquid formulation dosage forms for oral administration can be aqueoussuspensions selected from the group including, but not limited to,pharmaceutically acceptable aqueous oral dispersions, emulsions,solutions, elixirs, gels, and syrups. See, e.g., Singh et al.,Encyclopedia of Pharmaceutical Technology, 2^(nd) Ed., pp. 754-757(2002). In addition to the particles of a mast cell stabilizer, theliquid dosage forms may include additives, such as: (a) disintegratingagents; (b) dispersing agents; (c) wetting agents; (d) at least onepreservative, (e) viscosity enhancing agents, (f) at least onesweetening agent, and (g) at least one flavoring agent. In someembodiments, the aqueous dispersions can further include a crystallineinhibitor. In some embodiments, systemically effective amounts of mastcell stabilizers are achieved with liquid oral formulations by includingpermeation enhancers in the liquid oral formulations.

Examples of disintegrating agents for use in the aqueous suspensions anddispersions include, but are not limited to, a starch, e.g., a naturalstarch such as corn starch or potato starch, a pregelatinized starchsuch as National 1551 or Amijel®, or sodium starch glycolate such asPromogel® or Explotab®; a cellulose such as a wood product,methylcrystalline cellulose, e.g., Avicel®, Avicel® PH101, Avicel®PH102, Avicel® PH105, Elcema® P100, Emcocel®, Vivacel®, Ming Tia®, andSolka-Floc®, methylcellulose, croscarmellose, or a cross-linkedcellulose, such as cross-linked sodium carboxymethylcellulose(Ac-Di-Sol®), cross-linked carboxymethylcellulose, or cross-linkedcroscarmellose; a cross-linked starch such as sodium starch glycolate; across-linked polymer such as crospovidone; a cross-linkedpolyvinylpyrrolidone; alginate such as alginic acid or a salt of alginicacid such as sodium alginate; a clay such as Veegum® HV (magnesiumaluminum silicate); a gum such as agar, guar, locust bean, Karaya,pectin, or tragacanth; sodium starch glycolate; bentonite; a naturalsponge; a surfactant; a resin such as a cation-exchange resin; citruspulp; sodium lauryl sulfate; sodium lauryl sulfate in combinationstarch; and the like.

In some embodiments, the dispersing agents suitable for the aqueoussuspensions and dispersions described herein include, for example,hydrophilic polymers, electrolytes, Tween® 60 or 80, PEG,polyvinylpyrrolidone (PVP; commercially known as Plasdone®), and thecarbohydrate-based dispersing agents such as, for example,hydroxypropylcellulose and hydroxypropyl cellulose ethers (e.g., HPC,HPC-SL, and HPC-L), hydroxypropyl methylcellulose and hydroxypropylmethylcellulose ethers (e.g. HPMC K100, HPMC K4M, HPMC K15M, and HPMCK100M), carboxymethylcellulose sodium, methylcellulose,hydroxyethylcellulose, hydroxypropylmethyl-cellulose phthalate,hydroxypropylmethyl-cellulose acetate stearate, noncrystallinecellulose, magnesium aluminum silicate, triethanolamine, polyvinylalcohol (PVA), polyvinylpyrrolidone/vinyl acetate copolymer (Plasdone®,e.g., S-630), 4-(1,1,3,3-tetramethylbutyl)-phenol polymer with ethyleneoxide and formaldehyde (also known as tyloxapol), poloxamers (e.g.,Pluronics F68®, F88®, and F108®, which are block copolymers of ethyleneoxide and propylene oxide); and poloxamines (e.g., Tetronic 908®, alsoknown as Poloxamine 908®, which is a tetrafunctional block copolymerderived from sequential addition of propylene oxide and ethylene oxideto ethylenediamine (BASF Corporation, Parsippany, N.J.)). In otherembodiments, the dispersing agent is selected from a group notcomprising one of the following agents: hydrophilic polymers;electrolytes; Tween® 60 or 80; PEG; polyvinylpyrrolidone (PVP);hydroxypropylcellulose and hydroxypropyl cellulose ethers (e.g., HPC,HPC-SL, and HPC-L); hydroxypropyl methylcellulose and hydroxypropylmethylcellulose ethers (e.g. HPMC K100, HPMC K4M, HPMC K15M, HPMC K100M,and Pharmacoat® USP 2910 (Shin-Etsu)); carboxymethylcellulose sodium;methylcellulose; hydroxyethylcellulose; hydroxypropylmethyl-cellulosephthalate; hydroxypropylmethyl-cellulose acetate stearate;non-crystalline cellulose; magnesium aluminum silicate; triethanolamine;polyvinyl alcohol (PVA); 4-(1,1,3,3-tetramethylbutyl)-phenol polymerwith ethylene oxide and formaldehyde; poloxamers (e.g., Pluronics F68®,F88®, and F108®, which are block copolymers of ethylene oxide andpropylene oxide); or poloxamines (e.g., Tetronic 908®, also known asPoloxamine 908®).

Wetting agents suitable for the aqueous suspensions and dispersionsdescribed herein include, but are not limited to, cetyl alcohol,glycerol monostearate, polyoxyethylene sorbitan fatty acid esters (e.g.,the commercially available Tweens® such as e.g., Tween 20® and Tween 80®(ICI Specialty Chemicals)), and polyethylene glycols (e.g., Carbowaxs3350® and 1450®, and Carbopol 934® (Union Carbide)), oleic acid,glyceryl monostearate, sorbitan monooleate, sorbitan monolaurate,triethanolamine oleate, polyoxyethylene sorbitan monooleate,polyoxyethylene sorbitan monolaurate, sodium oleate, sodium laurylsulfate, sodium docusate, triacetin, vitamin E TPGS, sodiumtaurocholate, simethicone, phosphotidylcholine and the like.

Intranasal Formulations

Intranasal formulations are known in the art and are described in, forexample, U.S. Pat. Nos. 4,476,116, 5,116,817 and 6,391,452, each ofwhich is specifically incorporated by reference. The choice of suitablecarriers is highly dependent upon the exact nature of the nasal dosageform desired, e.g., solutions, suspensions, ointments, or gels. Nasaldosage forms generally contain large amounts of water in addition to theactive ingredient. Minor amounts of other ingredients such as pHadjusters, emulsifiers or dispersing agents, viscosity enhancing agents,preservatives, surfactants, gelling agents, or buffering and otherstabilizing and solubilizing agents may also be present. In someembodiments, the nasal dosage form is isotonic with nasal secretions. Insome embodiments a nasal dosage form is formulated to achieve sustaineddelivery. Examples of sustained delivery nasal dosage forms include, butare not limited to, dosage forms that include mucoadhesive agents suchas microcrystalline cellulose. In some embodiments, systemicallyeffective amounts of mast cell stabilizers are achieved with intranasalformulations by one or more of optimizing the droplet or particle sizeand including permeation enhancers in the intranasal formulation.

Buccal Formulations

Buccal formulations that include mast cell stabilizers may beadministered using a variety of formulations known in the art. Forexample, such formulations include, but are not limited to, thosedescribed in U.S. Pat. Nos. 4,229,447, 4,596,795, 4,755,386, and5,739,136, each of which is specifically incorporated by reference. Inaddition, the buccal dosage forms can further include a bioerodible(hydrolysable) polymeric carrier that also serves to adhere the dosageform to the buccal mucosa. The buccal dosage form is fabricated so as toerode gradually over a predetermined time period, wherein the deliveryof the mast cell stabilizer is provided essentially throughout. Buccaldrug delivery, as will be appreciated by those skilled in the art,avoids the disadvantages encountered with oral drug administration,e.g., slow absorption, degradation of the active agent by fluids presentin the gastrointestinal tract and/or first-pass inactivation in theliver. With regard to the bioerodible (hydrolysable) polymeric carrier,it will be appreciated that virtually any such carrier can be used, solong as the desired drug release profile is not compromised, and thecarrier is compatible with the mast cell stabilizer and any othercomponents that may be present in the buccal dosage unit. Generally, thepolymeric carrier comprises hydrophilic (water-soluble andwater-swellable) polymers that adhere to the wet surface of the buccalmucosa. Examples of polymeric carriers useful herein include acrylicacid polymers, e.g., those known as “carbomers” (Carbopol®, which may beobtained from B.F. Goodrich, is one such polymer). Other components mayalso be incorporated into the buccal dosage forms described hereininclude, but are not limited to, disintegrants, diluents, binders,lubricants, flavoring, colorants, preservatives, and the like. In someembodiments, systemically effective amounts of mast cell stabilizers areachieved with buccal formulations by one or more of optimizing theerosion time of the formulation and by including permeation enhancers inthe buccal formulations.

Transdermal Formulations

Transdermal formulations described herein may be administered using avariety of devices which have been described in the art. For example,such devices include, but are not limited to, those described in U.S.Pat. Nos. 3,598,122, 3,598,123, 3,710,795, 3,731,683, 3,742,951,3,814,097, 3,921,636, 3,972,995, 3,993,072, 3,993,073, 3,996,934,4,031,894, 4,060,084, 4,069,307, 4,077,407, 4,201,211, 4,230,105,4,292,299, 4,292,303, 5,336,168, 5,665,378, 5,837,280, 5,869,090,6,923,983, 6,929,801 and 6,946,144, each of which is specificallyincorporated by reference in its entirety.

Transdermal dosage forms for use in the methods disclosed herein mayincorporate certain pharmaceutically acceptable excipients which areconventional in the art. In one embodiment, the transdermal formulationsinclude at least three components: (1) a formulation of a mast cellstabilizer; (2) a penetration enhancer; and (3) an aqueous adjuvant. Inaddition, transdermal formulations can include additional componentssuch as, but not limited to, gelling agents, creams and ointment bases,and the like. In some embodiments, the transdermal formulation canfurther include a woven or non-woven backing material to enhanceabsorption and prevent the removal of the transdermal formulation fromthe skin. In other embodiments, the transdermal formulations describedherein can maintain a saturated or supersaturated state to promotediffusion into the skin. In some embodiments, systemically effectiveamounts of mast cell stabilizers are achieved with transdermal dosageforms by including skin permeation enhancers in the transdermal dosageforms.

Transdermal formulations used in the methods described herein may employtransdermal delivery devices and transdermal delivery patches and can belipophilic emulsions or buffered, aqueous solutions, dissolved and/ordispersed in a polymer or an adhesive. Such patches may be constructedfor continuous, pulsatile, or on demand delivery of pharmaceuticalagents. Still further, transdermal delivery of mast cell stabilizers canbe accomplished by means of iontophoretic patches, microneedle systems,and the like. Additionally, transdermal patches can provide controlleddelivery of the mast cell stabilizer. The rate of absorption can beslowed by using rate-controlling membranes or by trapping the compoundwithin a polymer matrix or gel. Conversely, absorption enhancers can beused to increase absorption. An absorption enhancer or carrier caninclude absorbable pharmaceutically acceptable solvents to assistpassage through the skin. For example, transdermal devices are in theform of a bandage comprising a backing member, a reservoir containingthe compound optionally with carriers, optionally a rate controllingbarrier to deliver the compound to the skin of the host at a controlledand predetermined rate over a prolonged period of time, and means tosecure the device to the skin. In some embodiments, transdermal deliveryof a mast cell stabilizer, e.g., cromolyn sodium, is provided usingtopical formulations of the mast cell stabilizer, e.g, cromolyn sodium.

Injectable Formulations

Formulations that include a mast cell stabilizer suitable forintramuscular, subcutaneous, or intravenous injection may containphysiologically acceptable sterile aqueous or non-aqueous solutions,dispersions, suspensions or emulsions, and sterile powders forreconstitution into sterile injectable solutions or dispersions.Examples of suitable aqueous and non-aqueous carriers, diluents,solvents, or vehicles including water, ethanol, polyols(propyleneglycol, polyethylene-glycol, glycerol, cremophor and thelike), suitable mixtures thereof, vegetable oils (such as olive oil) andinjectable organic esters such as ethyl oleate. Proper fluidity can bemaintained, for example, by the use of a coating such as lecithin, bythe maintenance of the required particle size in the case ofdispersions, and by the use of surfactants. Formulations suitable forsubcutaneous injection may also contain additives such as preserving,wetting, emulsifying, and dispensing agents. Prevention of the growth ofmicroorganisms can be ensured by various antibacterial and antifungalagents, such as parabens, chlorobutanol, phenol, sorbic acid, and thelike. It may also be desirable to include isotonic agents, such assugars, sodium chloride, and the like. Prolonged absorption of theinjectable pharmaceutical form can be brought about by the use of agentsdelaying absorption, such as aluminum monostearate and gelatin.

For intravenous injections, compounds described herein may be formulatedin aqueous solutions, preferably in physiologically compatible bufferssuch as Hank's solution, Ringer's solution, or physiological salinebuffer. For transmucosal administration, penetrants appropriate to thebarrier to be permeated are used in the formulation. Such penetrants aregenerally known in the art. For other parenteral injections, appropriateformulations may include aqueous or nonaqueous solutions, preferablywith physiologically compatible buffers or excipients. Such excipientsare generally known in the art.

Parenteral injections may involve bolus injection or continuousinfusion. Pharmaceutical formulations for parenteral administrationinclude aqueous solutions of the mast cell stabilizers in water-solubleform. Additionally, suspensions of the mast cell stabilizers may beprepared as appropriate oily injection suspensions. Suitable lipophilicsolvents or vehicles include fatty oils such as sesame oil, or syntheticfatty acid esters, such as ethyl oleate or triglycerides, or liposomes.Aqueous injection suspensions may contain substances which increase theviscosity of the suspension, such as sodium carboxymethyl cellulose,sorbitol, or dextran. Optionally, the suspension may also containsuitable stabilizers or agents which increase the solubility of thecompounds to allow for the preparation of highly concentrated solutions.Alternatively, the active ingredient may be in powder form forconstitution with a suitable vehicle, e.g., sterile pyrogen-free water,before use. In some embodiments, parenteral formulations are prepared toprovide sustained release of a mast cell stabilizer. In someembodiments, sustained release is provided by incorporating liposomes,stealth liposomes, bioerodible polymers, and the like into parenteralformulations to maximize the residence time in circulation and/or toincrease absorption of the mast cell stabilizer.

Implantable Formulations

Formulations that include a mast cell stabilizer suitable forimplantation may contain physiologically acceptable sterile aqueous ornon-aqueous solutions, dispersions, suspensions, or emulsions. In someembodiments, the formulations are contained in and delivered from anosmotic pump implant to achieve sustained delivery of the mast cellstabilizer over long durations. In some embodiments, a mast cellstabilizer is formulated with a bioerodible polymer, which, uponadministration facilitates the formation of a depot containing the mastcell stabilizer. The depot would then erode and release the mast cellstabilizer over a duration determined by the composition of thebioerodible polymer. In some embodiments, viscosity modifying agents,stabilizers, and other excipients may be used in the formulation toachieve optimum delivery over an extended duration.

Inhalation Therapy

An “inhalation device,” as used herein, refers to any device that iscapable of administering a drug formulation to the respiratory airwaysof a patient. Inhalation devices include conventional inhalation devicessuch as metered dose inhalers (MDIs), dry powder inhalers (DPIs), jetnebulizers, ultrasonic wave nebulizers, heat vaporizers, and soft mistinhalers. Inhalation devices also include high efficiency nebulizers.Nebulizers, metered dose inhalers, and soft mist inhalers deliverpharmaceuticals by forming an aerosol which includes droplet sizes thatcan easily be inhaled. The aerosol can be used by a patient within thebounds of an inhalation therapy, whereby the mast cell stabilizerreaches the patient's respiratory tract upon inhalation. In someembodiments, the methods disclosed herein comprise administering to apatient a nominal dose of a mast cell stabilizer by an inhalationdevice. In some embodiments of the methods disclosed herein, aninhalation device is not a bronchoscope.

In some embodiments of the methods disclosed herein, administration of acomposition comprising a mast cell stabilizer, e.g., cromolyn sodium, toa patient with an inhalation device, e.g., a high efficiency nebulizer,a dry powder inhaler, a metered dose inhaler, a thermal aerosol inhaler,or an electrohydrodynamic-based solution misting inhaler, is effectivefor the treatment or prophylaxis of a systemic mast cell relateddisorder because both a systemically effective amount of the mast cellstabilizer and a high deposited lung dose of the mast cell stabilizer isachieved in the patient. Thus, in some embodiments of the methodsdisclosed herein, administration of a composition comprising a mast cellstabilizer, e.g., cromolyn sodium, to a patient with an inhalationdevice, e.g., a high efficiency nebulizer, a dry powder inhaler, ametered dose inhaler, a thermal aerosol inhaler, or anelectrohydrodynamic-based solution misting inhaler, is effective for thetreatment or prophylaxis of a systemic mast cell related disorder thatis not believed to be susceptible to treatment or prophylaxis with amast cell stabilizer because both a systemically effective amount of themast cell stabilizer and a high deposited lung dose of the mast cellstabilizer are achieved in the patient. Furthermore, in some embodimentswhere a mast cell stabilizer is administered with an inhalation device,e.g., a high efficiency nebulizer, a dry powder inhaler, a metered doseinhaler, a thermal aerosol inhaler, or an electrohydrodynamic-basedsolution misting inhaler, the methods disclosed herein provide improvedefficacy for the treatment or prophylaxis of a systemic mast cellrelated disorder relative to administration of a systemically effectiveamount of the mast cell stabilizer by a different route ofadministration, e.g., parenterally or orally, because administration ofthe mast cell stabilizer with an inhalation device, e.g., a highefficiency nebulizer, a dry powder inhaler, a metered dose inhaler, athermal aerosol inhaler, or an electrohydrodynamic-based solutionmisting inhaler, provides both a systemically effective amount of themast cell stabilizer and a high deposited lung dose of the mast cellstabilizer in the patient. In some embodiments, a systemically effectiveamount of a mast cell stabilizer is achieved by delivering the mast cellstabilizer in an aerosol generated by a vibrating mesh nebulizer thatproduces droplets with a MMD of 3.0-4.0 μm and a GSD of 1.5-1.8. In someembodiments of the methods disclosed herein, an aerosol is administeredthrough a mouthpiece of a nebulizer using normal tidal breathing.

Characterization of Inhalation Devices

The efficiency of a particular inhalation device can be characterized inmany different ways, including by pharmacokinetic properties, lungdeposition (deposited lung dose), respirable dose (RD), delivered dose(DD), respirable fraction (RF), respirable drug delivery rate (RDDR),volumetric or mass median diameter (VMD or MMD), mass median aerodynamicdiameter (MMAD) in combination with the geometric standard deviation(GSD), and total output rate (TOR), among others. The MMAD and GSD canbe measured using a cascade impactor as described in United StatesPhamacopeia (USP<1601>). The DD can be measured by using breathsimulation apparatus as described in USP<1601>. The RF is derived frommeasuring the amount of drug deposited on the cascade impactor plateswith a particular cut-off particle size, and expressing that as afraction of the total amount deposited on the cascade impactor plates,the induction port and the filter. The RD is calculated by multiplyingthe DD by the RF. The TOR is measured by the difference in weight of thenebulizer before and after completion of nebulization divided by theduration of nebulization. VIVID or MMD can be measured with a standardlaser light scattering apparatus such as the Malvern Spraytec.

Pharmacokinetics is concerned with the uptake, distribution, metabolismand excretion of a drug substance. A pharmacokinetic profile comprisesone or more biological measurements designed to measure the absorption,distribution, metabolism and excretion of a drug substance. One way ofvisualizing a pharmacokinetic profile is by means of a blood plasmaconcentration curve, which is a graph depicting mean active ingredientblood plasma concentration on the Y-axis and time (usually in hours) onthe X-axis. Some pharmacokinetic parameters that may be visualized bymeans of a blood plasma concentration curve include AUC_(last),AUC_((0-∞)), C_(max), T_(1/2), and T_(max). An enhanced pharmacokineticprofile in a patient can be indicated by increased AUC_(last),AUC_((0-∞)), C_(max), or T_(1/2), a decreased T_(max), or an increasedT_(max). Enhanced levels of a mast cell stabilizer in the blood plasmaof a patient may result in better control of or improved symptoms of asystemic mast cell related disorder.

The deposited lung dose may be expressed as a percentage of the nominaldose that is deposited in the lung. For example, a lung deposition of30% means 30% of the nominal dose is deposited in the lung. Likewise, alung deposition of 60% means 60% of the nominal dose is deposited in thelung, and so forth. Lung deposition (deposited lung dose) can bedetermined using methods of scintigraphy or deconvolution.

RF, DD, RD, and RDDR are calculated parameters based on in vitro datathat provide technical dimensions for the efficiency of an inhalationdevice. RF represents the percentage of the delivered aerosol, orinhaled mass, that penetrates into the gas-exchange region of the lungs.RF may be measured with a cascade impactor or laser diffractionapparatus. RF is expressed herein as the percentage of an aerosoldelivered with an inhalation device that has a particular particlediameter or range of particle diameters. For example, the term “RF (≤3.3μm)” as used herein refers to the percentage of an aerosol deliveredwith an inhalation device that has a particle diameter less than orequal to 3.3 μm. Similarly, the terms “RF (1-5 μm)” and “RF (≤5 μm)” asused herein refer to the percentage of an aerosol delivered with aninhalation device that has a particle diameter in the range of 1 μm to 5μm, or less than 5 μm, respectively. DD is the portion or percentage ofthe nominal dose that is actually emitted from the mouthpiece of thedevice. The difference between the nominal dose and the DD is the amountof drug lost primarily as residues, i.e., the amount of drug remainingin the inhalation device after administration or lost in aerosol form.RD is an expression of the delivered mass of drug contained withindroplets or particles having a certain diameter emitted from aninhalation device, such as a DPI, MDI, or nebulizer, that are smallenough to penetrate into the lung of a patient. The RD is determined bymultiplying the DD by the RF. RDDR is the speed at which a respirabledose of the drug is delivered to a patient's lungs. RDDR, measured as afunction of μg or mg/min, is determined by dividing the RD by the amountof time necessary for inhalation. The amount of time necessary forinhalation is measured as the amount of time from the first moment ofadministration of the emitted droplet or powder from the nebulizer, DPI,or MDI until the emitted or delivered droplet or powder of a respirablediameter is delivered to the lung.

Aerosol particle/droplet size is one factor determining the depositionof aerosol drugs in the airways. The distribution of aerosolparticle/droplet size can be expressed in terms of one or more ofVMD/MMAD and GSD. GSD is a dimensionless measure of a droplet sizedistribution curve relevant for characterizing terms such as VMD, MMD,and MMAD. In general, the smaller the GSD for a particular particle sizedistribution, the narrower the distribution curve.

Conventional Inhalation Devices

Conventional inhalation devices may be mechanical or electrical, andinclude, for example, jet nebulizers and ultrasonic nebulizers. Jetnebulizers generally utilize compressors to generate compressed air,which breaks the liquid medication into small breathable droplets, whichform an aerosolized (atomized) mist. In some embodiments, when thepatient breathes in, a valve at the top opens, which then allows airinto the apparatus, thereby speeding up the mist generation; when thepatient breathes out, the top valve closes, thereby slowing down themist generation while simultaneously permitting the patient to breatheout through the opening of a mouthpiece flap. Some nebulizers mayprovide the aerosol in a continuous mode (e.g., the eFlow from PARIPharma Starnberg), by a breath enhanced mode (e.g., the PARI LC Plus orSprint from PARI Starnberg), by breath actuated mode dependent on thebreathing pattern of the patient (e.g., the AeroEclipse from Trudell,Canada or the I-Neb from Philips Respironics), or according to giveninhalation profile (e.g., the Akita from Activaero, Gmuenden, Germany).

Some conventional inhalation devices are disclosed in U.S. Pat. Nos.6,513,727, 6,513,519, 6,176,237, 6,085,741, 6,000,394, 5,957,389,5,740,966, 5,549,102, 5,461,695, 5,458,136, 5,312,046, 5,309,900,5,280,784, and 4,496,086, each of which is hereby incorporated byreference in its entirety. Commercial conventional inhalation devicesare available from: PARI (Germany) under the trade names PARI LC Plus®,LC Star®, and PARI-Jet®; A & H Products, Inc. (Tulsa, Okla.) under thetrade name AquaTower®; Hudson RCI (Temecula, Calif.) under the tradename AVA-NEB®; Intersurgical, Inc. (Liverpool, N.Y.) under the tradename Cirrus®; Salter Labs (Arvin, Calif.) under the trade name Salter8900®; Respironics (Murrysville, Pa.) under the trade name Sidestream®;Bunnell (Salt Lake City, Utah) under the trade name Whisper Jet®;Smiths-Medical (Hyth Kent, UK) under the trade name Downdraft®, andDeVilbiss (Somerset, Pa.) under the trade name DeVilbiss®; or Trudell,Canada under the trade name AeroEclipse®.

In some embodiments of the methods disclosed herein, compositionscomprising mast cell stabilizers are administered with a dry powderinhaler. In some embodiments of the methods disclosed herein,compositions administered with dry powder inhalers comprise one or moreof nanoparticles, spray dried materials, engineered porous particleswith low mass median diameter but a high geometric diameter, liposomes,and stealth (or PEGylated) liposomes. In some embodiments, compositionsadministered by dry powder inhalers administered in the methodsdisclosed herein comprise nanoparticle clusters that aggregate intomicrometer sized particles at neutral or basic pH but dissociate intonanoparticles at the pH encountered in the lung. In some embodiments thenanoparticle clusters comprise fumaryl diketopiperazine. In someembodiments, compositions administered with dry powder inhalers compriselactose. In some embodiments, compositions administered with dry powderinhalers do not comprise lactose. In some embodiments, compositionsadministered with a dry powder inhaler have a MMAD between 2 and 4 μm, aGSD between 1.5 and 2.5 μm, and an RF(≤5 μm) between 30% and 80%. Insome embodiments, a dry powder inhaler used to administer an inhalationformulation in the methods disclosed herein comprises a pre-metereddose, such as Plastiape Monodose inhaler, which comprises a capsulepre-filled with a powder. In some embodiments, a dry powder inhaler usedto administer an inhalation formulation in the methods disclosed hereinhas a device-metered system such as Twisthaler, sold by Schering Plough,which comprises a reservoir to store a powder and a twisting top todispense each dose. Inhalation formulations for administration with adry powder inhaler may be prepared by blending a mast cell stabilizer,e.g., cromolyn sodium, with lactose, or spray drying a mast cellstabilizer, e.g., cromolyn sodium, or by pelletizing a mast cellstabilizer, e.g., cromolyn sodium, to form free-flowing sphericalagglomerates.

In some embodiments of the methods disclosed herein, compositionscomprising mast cell stabilizers are administered with a metered doseinhaler. In some embodiments, a composition administered with a metereddose inhaler in the methods disclosed herein comprises one or more ofnanoparticles, spray dried materials, engineered porous particles withlow mass median diameter but a high geometric diameter, liposomes, andstealth (or PEGylated) liposomes.

In some embodiments of the methods disclosed herein, compositionscomprising mast cell stabilizers are administered with a thermal aerosolinhaler. In some embodiments, the aerosol in a thermal aerosol inhaleris generated by directly heating and vaporizing a thin solid film of themast cell stabilizer, e.g., cromolyn sodium, or by heating andvaporizing a solution of a mast cell stabilizer, e.g., cromolyn sodiumin solvents such as propylene glycol and/or glycerol and water.

In some embodiments of the methods disclosed herein, compositionscomprising mast cell stabilizers are administered with anelectrohydrodynamic-based solution misting inhaler. In some embodiments,the aerosol in the electrohydrodynamic-based solution-misting inhaler isgenerated by subjecting a solution of a mast cell stabilizer, e.g.,cromolyn sodium, or a liposome or pegylated liposome comprising a mastcell stabilizer, e.g., cromolyn sodium, to electrohydrodynamic forcesthrough electrostatic energy.

High Efficiency Nebulizers

High efficiency nebulizers are inhalation devices that comprise amicro-perforated membrane through which a liquid solution is convertedthrough electrical or mechanical means into aerosol droplets suitablefor inhalation. High efficiency nebulizers can deliver a large fractionof a loaded dose to a patient. In some embodiments, the high efficiencynebulizer also utilizes one or more actively or passively vibratingmicroperforated membranes. In some embodiments, the high efficiencynebulizer contains one or more oscillating membranes. In someembodiments, the high efficiency nebulizer contains a vibrating mesh orplate with multiple apertures and optionally a vibration generator withan aerosol mixing chamber. In some such embodiments, the mixing chamberfunctions to collect (or stage) the aerosol from the aerosol generator.In some embodiments, an inhalation valve is also used to allow an inflowof ambient air into the mixing chamber during an inhalation phase and isclosed to prevent escape of the aerosol from the mixing chamber duringan exhalation phase. In some such embodiments, the exhalation valve isarranged at a mouthpiece which is removably mounted at the mixingchamber and through which the patient inhales the aerosol from themixing chamber. Still yet, in some embodiments, the high efficiencynebulizer contains a pulsating membrane. In some embodiments, the highefficiency nebulizer is continuously operating.

In some embodiments, the high efficiency nebulizer contains a vibratingmicro-perforated membrane of tapered nozzles that generates a plume ofdroplets without the need for compressed gas. In these embodiments, asolution in the micro-perforated membrane nebulizer is in contact with amembrane, the opposite side of which is open to the air. The membrane isperforated by a large number of nozzle orifices of an atomizing head. Anaerosol is created when alternating acoustic pressure in the solution isbuilt up in the vicinity of the membrane causing the fluid on the liquidside of the membrane to be emitted through the nozzles as uniformlysized droplets.

Some embodiments of high efficiency nebulizers use passive nozzlemembranes and a separate piezoelectric transducer that stimulates themembrane. In contrast, some high efficiency nebulizers employ an activenozzle membrane, which use the acoustic pressure in the nebulizer togenerate very fine droplets of solution via the high frequency vibrationof the nozzle membrane.

Some high efficiency nebulizers contain a resonant system. In some suchhigh efficiency nebulizers, the membrane is driven by a frequency forwhich the amplitude of the vibrational movement at the center of themembrane is particularly large, resulting in a focused acoustic pressurein the vicinity of the nozzle; the resonant frequency may be about 100kHz. A flexible mounting is used to keep unwanted loss of vibrationalenergy to the mechanical surroundings of the atomizing head to aminimum. In some embodiments, the vibrating membrane of the highefficiency nebulizer may be made stainless steel, or of anickel-palladium alloy by electroforming.

In some embodiments, a high efficiency nebulizer may be adapted oradaptable to operate in conjunction with a unit dosage form, such as anampule or vial, which contains a single dose of a mast cell stabilizercomposition for the treatment of a systemic mast cell related disorder.The unit dosage form comprises a container that contains an inhalationformulation comprising the mast cell stabilizer, such as cromolynsodium. The container is adapted to cooperate with the high efficiencynebulizer device in such a way as to permit administration of thenominal dose of the inhalation formulation to a patient. In someembodiments, the high efficiency nebulizer and the unit dosage form areconfigured so that they are useable together, but not with other devicesor dosage forms. In some particular embodiments, the unit dosage form isconfigured such that it fits into a keyhole-like structure in the highefficiency nebulizer, but will not operate with other nebulizer devices.In such embodiments, the high efficiency nebulizer is configured suchthat it will accept and properly operate with the unit dosage formcontaining the mast cell stabilizer, but not with other dosage forms.

Commercial high efficiency nebulizers are available from: PARI (Germany)under the trade name eFlow®; Aerogen, Ltd. (Ireland) under the tradenames AeroNeb® Go and AeroNeb® Pro, AeroNeb® Solo, and other nebulizersutilizing the OnQ® nebulizer technology; Respironics (Murrysville,Calif.) under the trade names I-Neb®; Omron (Bannockburn, Ill.) underthe trade name Micro-Air®; Activaero (Germany) under the trade nameAkita®, and AerovectRx (Atlanta, Ga.) under the trade name AerovectRx®.

In some embodiments, the methods disclosed herein compriseadministration to a patient a nominal dose of a mast cell stabilizerwith a high efficiency nebulizer, wherein administration of the nominaldose of the mast cell stabilizer to the patient provides one or more ofthe following advantages: (1) an enhanced pharmacokinetic profile ascompared to administration of an oral solution or an inhalationformulation with a conventional inhalation device; (2) an enhancedtherapeutic effect as compared to administration of an oral solution oran inhalation formulation with a conventional inhalation device; (3) anenhanced lung deposition (deposited lung dose) as compared with aconventional inhalation device evidenced by scintigraphy ordeconvolution, or derived from suitable in vitro indicators such asenhanced RD, RDDR, RF, and lower GSDs, as compared to administrationwith a conventional inhalation device; (4) reduced administration times,periods, and/or volumes as compared to administration with aconventional inhalation device; (5) a reduction in adverse side effectsassociated with oral formulations of a mast cell stabilizer, such asgastrointestinal irritation, or associated with conventional inhalationdevices, such as cough; and (6) a longer duration of therapeutic effectas compared to administration of an oral solution or an inhaledformulation with a conventional inhalation device.

In some embodiments, the DD expressed as the percentage of the nominaldose of a mast cell stabilizer administered with a high efficiencynebulizer in the methods disclosed herein is at least about 30%, atleast about 35%, at least about 40%, at least about 45%, at least about50%, at least about 55%, at least about 60%, at least about 65%, about65%, about 70%, about 30% to about 90%, about 40% to about 80%, about45% to about 75%, about 50% to about 70%, about 30% to about 75%, about40% to about 70%, about 45% to about 60%, or about 60% to about 70%.

TOR is the speed at which the liquid containing a mast cell stabilizeris administered from the inhalation device. In some embodiments,administration of the mast cell stabilizer with the high efficiencynebulizer provides a TOR of at least about 2 times, 3 times or 4 timesthe TOR achievable with a conventional inhalation device, such as anebulizer. For example, in some embodiments the TOR is at least about atleast about 150 mg/min, at least about 200 mg/min, at least about 250mg/min, at least 300 mg/min, at least 350 mg/min, at least 400 mg/min,at least 500 mg/min, or from 200 to about 700 mg/min.

In some embodiments, use of a high efficiency nebulizer in the methodsdisclosed herein provides a RF (≤3.3 μm) of mast cell stabilizer of atleast about 20%, at least about 25%, at least about 30%, at least about35%, at least about 40%, at least about 45%, at least about 50%, atleast about 55%, at least about 60%, at least about 65%, at least about70%, at least about 75%, at least about 80%, at least about 85%, atleast about 90%, at least about 95%, about 20% to about 95%, about 35%to about 90%, or about 40% to about 80%, about 40% to about 90%, about40% to about 95%, about 45% to about 90%, about 45% to about 95%, about50% to about 90%, about 65% to about 90%, about 60% to about 95%, about65% to about 95%, about 70% to about 90%, or about 55% to about 90%. Insome embodiments, use of a high efficiency nebulizer in the methodsdisclosed herein provides a RF (≤3.3 μm) of cromolyn sodium of at leastabout 20%, at least about 25%, at least about 30%, at least about 35%,at least about 40%, at least about 45%, at least about 50%, at leastabout 55%, at least about 60%, at least about 65%, at least about 70%,at least about 75%, at least about 80%, at least about 85%, at leastabout 90%, at least about 95%, about 20% to about 95%, about 35% toabout 90%, or about 40% to about 80%, about 40% to about 90%, about 40%to about 95%, about 45% to about 90%, about 45% to about 95%, about 50%to about 90%, about 65% to about 90%, about 60% to about 95%, about 65%to about 95%, about 70% to about 90%, about 55% to about 90%, about 40%to about 50%, about 35% to about 45%, about 35% to about 50%, about 30%to about 50%, about 44%, or about 36%.

In some embodiments, use of a high efficiency nebulizer in the methodsdisclosed herein provides a RF (1-5 μm) of mast cell stabilizer of atleast about 20%, at least about 25%, at least about 30%, at least about35%, at least about 40%, at least about 45%, at least about 50%, atleast about 55%, at least about 60%, at least about 65%, at least about70%, at least about 75%, at least about 80%, at least about 85%, atleast about 90%, at least about 95%, about 20% to about 95%, about 35%to about 90%, or about 40% to about 80%, about 40% to about 90%, about40% to about 95%, about 45% to about 90%, about 45% to about 95%, about50% to about 90%, about 65% to about 90%, about 60% to about 95%, about65% to about 95%, about 70% to about 90%, or about 55% to about 90%. Insome embodiments, use of a high efficiency nebulizer in the methodsdisclosed herein provides a RF (1-5 μm) of cromolyn sodium of at leastabout 20%, at least about 25%, at least about 30%, at least about 35%,at least about 40%, at least about 45%, at least about 50%, at leastabout 55%, at least about 60%, at least about 65%, at least about 70%,at least about 75%, at least about 80%, at least about 85%, at leastabout 90%, at least about 95%, about 20% to about 95%, about 35% toabout 90%, or about 40% to about 80%, about 40% to about 90%, about 40%to about 95%, about 45% to about 90%, about 45% to about 95%, about 50%to about 90%, about 65% to about 90%, about 60% to about 95%, about 65%to about 95%, about 70% to about 90%, or about 55% to about 90%.

In some embodiments, use of a high efficiency nebulizer in the methodsdisclosed herein provides a RF (≤5 μm) of mast cell stabilizer of atleast about 20%, at least about 25%, at least about 30%, at least about35%, at least about 40%, at least about 45%, at least about 50%, atleast about 55%, at least about 60%, at least about 65%, at least about70%, at least about 75%, at least about 80%, at least about 85%, atleast about 90%, at least about 95%, about 20% to about 95%, about 35%to about 90%, or about 40% to about 80%, about 40% to about 90%, about40% to about 95%, about 45% to about 90%, about 45% to about 95%, about50% to about 90%, about 65% to about 90%, about 60% to about 95%, about65% to about 95%, about 70% to about 90%, about 55% to about 90%, about70% to about 80%, or about 75%. In some embodiments, use of a highefficiency nebulizer in the methods disclosed herein provides a RF (≤5μm) of cromolyn sodium of at least about 20%, at least about 25%, atleast about 30%, at least about 35%, at least about 40%, at least about45%, at least about 50%, at least about 55%, at least about 60%, atleast about 65%, at least about 70%, at least about 75%, at least about80%, at least about 85%, at least about 90%, at least about 95%, about20% to about 95%, about 35% to about 90%, or about 40% to about 80%,about 40% to about 90%, about 40% to about 95%, about 45% to about 90%,about 45% to about 95%, about 50% to about 90%, about 65% to about 90%,about 60% to about 95%, about 65% to about 95%, about 70% to about 90%,about 55% to about 90%, about 70% to about 80%, about 65% to about 75%,about 65% to about 80%, about 60% to about 80%, about 66%, or about 75%.

In some embodiments, use of a high efficiency nebulizer in the methodsdisclosed herein provides a RDDR of at least about 2 times, at leastabout 3 times or at least about 4 times the RDDR achievable with aconventional inhalation device. For example, where the mast cellstabilizer is cromolyn sodium, in some embodiments the RDDR is at leastabout 5 mg/min, at least about 10 mg/min, at least about 15 mg/min, atleast about 20 mg/min, at least about 25 mg/min, at least about 30mg/min, at least about 35 mg/min, at least about 40 mg/min, at leastabout 45 mg/min, at least about 50 mg/min, at least about 55 mg/min, orat least about 60 mg/min.

In some embodiments, administration of a mast cell stabilizer with ahigh efficiency nebulizer in the methods disclosed herein provides a GSDof emitted droplet size distribution of about 1.1 to about 2.1, about1.2 to about 2.0, about 1.3 to about 1.9, less than about 2, at leastabout 1.4 to about 1.8, at least about 1.5 to about 1.7, about 1.4,about 1.5, about 1.6, or about 1.7. In some embodiments, administrationof a mast cell stabilizer with a high efficiency nebulizer in themethods disclosed herein provides a MMAD of droplet size of about 1 μmto about 5 μm, about 2 to about 4 μm, about 3 to about 4 μm, about 3.5to about 4.5 μm, or about 3.5 μm. In some particular embodiments,administration of a mast cell stabilizer in the methods disclosed hereinprovides droplets having a particular combination of MMAD and GSD, forexample: an MMAD of less than about 5 μm and a GSD of about 1.1 to about2.1; an MMAD of less than about 4.5 μm and a GSD of about 1.1 to about2.1; an MMAD of about 1 μm to about 5 μm and a GSD of about 1.1 to about2.1; an MMAD of about 1.5 to about 4.5 μm and a GSD of about 1.1 toabout 2.1; an MMAD of less than about 5 μm and a GSD of about 1.1 toabout 2.0; an MMAD of less than about 4.5 μm and a GSD of about 1.1 toabout 2.0; an MMAD of about 1 μm to about 5 μm and a GSD of about 1.1 toabout 2.0; an MMAD of about 1.5 to about 4.5 μm and a GSD of about 1.1to about 2.0; an MMAD of less than about 5 μm and a GSD of about 1.1 toabout 1.9; an MMAD of less than about 4.5 μm and a GSD of about 1.1 toabout 1.9; an MMAD of about 1 μm to about 5 μm and a GSD of about 1.1 toabout 1.9; an MMAD of about 1.5 to about 4.5 μm and a GSD of about 1.1to about 1.9; an MMAD of less than about 5 μm and a GSD of about 1.1 toabout 1.8; an MMAD of less than about 4.5 μm and a GSD of about 1.1 toabout 1.8; an MMAD of about 1 μm to about 5 μm and a GSD of about 1.1 toabout 1.8; an MMAD of about 1.5 to about 4.5 μm and a GSD of about 1.1to about 1.8; an MMAD of about 3.5 μm or less and a GSD of about 1.7; anMMAD of about 4.1 μm or less and a GSD of about 1.7; an MMAD of about3.5 μm and a GSD of about 1.7; or an MMAD of about 4.1 μm and a GSD ofabout 1.7.

In some embodiments, the median particle size of a mast cell stabilizeraerosol administered with a high efficiency nebulizer is between about 1μm and about 6 μm, between about 2 μm and about 5 μm, between about 3 μmand about 5 μm, between about 3 μm and about 4 μm, about 1 μm, about 2μm, about 3 μm, about 4 μm, about 5 μm, or about 6 μm. In someembodiments, the median particle size of cromolyn sodium aerosoladministered with a high efficiency nebulizer is between about 1 μm andabout 6 μm, between about 2 μm and about 5 μm, between about 3 μm andabout 5 μm, between about 3 μm and about 4 μm, about 1 μm, about 2 μm,about 3 μm, about 4 μm, about 5 μm, or about 6 μm.

Inhalation Formulations

In some embodiments of the methods disclosed herein, inhalationformulations are administered by an inhalation device, e.g., a highefficiency nebulizer, to provide a systemically effective amount of amast cell stabilizer for the treatment of a systemic mast cell relateddisorder. In some embodiments, the methods disclosed herein compriseadministering a nominal dose of one or more mast cell stabilizers in anaqueous inhalation solution to the patient with an inhalation device,e.g., a high efficiency nebulizer.

In some embodiments of the methods disclosed herein, an inhalationformulation administered with an inhalation device, e.g., a highefficiency nebulizer, produces in a human subject group an averageAUC_((0-∞)) of a mast cell stabilizer greater than about 100 ng*hr/mL,greater than about 110 ng*hr/mL, greater than about 120 ng*hr/mL,greater than about 130 ng*hr/mL, greater than about 140 ng*hr/mL,greater than about 150 ng*hr/mL, greater than about 160 ng*hr/mL,greater than about 170 ng*hr/mL, greater than about 180 ng*hr/mL,greater than about 190 ng*hr/mL, greater than about 200 ng*hr/mL,greater than about 225 ng*hr/mL, greater than about 250 ng*hr/mL,greater than about 275 ng*hr/mL, greater than about 300 ng*hr/mL,greater than about 325 ng*hr/mL, greater than about 350 ng*hr/mL,greater than about 375 ng*hr/mL, greater than about 400 ng*hr/mL,greater than about 425 ng*hr/mL, greater than about 450 ng*hr/mL,greater than about 475 ng*hr/mL, greater than about 500 ng*hr/mL,greater than about 525 ng*hr/mL, greater than about 550 ng*hr/mL,greater than about 575 ng*hr/mL, greater than about 600 ng*hr/mL,greater than about 625 ng*hr/mL, greater than about 650 ng*hr/mL,greater than about 675 ng*hr/mL, greater than about 700 ng*hr/mL,greater than about 725 ng*hr/mL, greater than about 750 ng*hr/mL,greater than about 775 ng*hr/mL, greater than about 800 ng*hr/mL,greater than about 825 ng*hr/mL, greater than about 850 ng*hr/mL,greater than about 875 ng*hr/mL, greater than about 900 ng*hr/mL,greater than about 925 ng*hr/mL, greater than about 950 ng*hr/mL,greater than about 975 ng*hr/mL, or greater than about 1000 ng*hr/mLafter administration of the formulation to the patient. In someembodiments of the methods disclosed herein, an inhalation formulationadministered with an inhalation device, e.g., a high efficiencynebulizer, produces in a human subject group an average AUC_((0-∞)) of amast cell stabilizer of about 100 ng*hr/mL, about 110 ng*hr/mL, about120 ng*hr/mL, about 130 ng*hr/mL, about 140 ng*hr/mL, about 150ng*hr/mL, about 160 ng*hr/mL, about 170 ng*hr/mL, about 180 ng*hr/mL,about 190 ng*hr/mL, about 200 ng*hr/mL, about 225 ng*hr/mL, about 250ng*hr/mL, about 275 ng*hr/mL, about 300 ng*hr/mL, about 325 ng*hr/mL,about 350 ng*hr/mL, about 375 ng*hr/mL, about 400 ng*hr/mL, about 425ng*hr/mL, about 450 ng*hr/mL, about 475 ng*hr/mL, about 500 ng*hr/mL,about 525 ng*hr/mL, about 550 ng*hr/mL, about 575 ng*hr/mL, about 600ng*hr/mL, about 625 ng*hr/mL, about 650 ng*hr/mL, about 675 ng*hr/mL,about 700 ng*hr/mL, about 725 ng*hr/mL, about 750 ng*hr/mL, about 775ng*hr/mL, about 800 ng*hr/mL, about 825 ng*hr/mL, about 850 ng*hr/mL,about 875 ng*hr/mL, about 900 ng*hr/mL, about 925 ng*hr/mL, about 950ng*hr/mL, about 975 ng*hr/mL, or about 1000 ng*hr/mL afteradministration of the formulation to the patient.

In some embodiments of the methods disclosed herein, an inhalationformulation administered with an inhalation device, e.g., a highefficiency nebulizer, produces in a human subject group an averageAUC_((0-∞)) of cromolyn sodium greater than about 100 ng*hr/mL, greaterthan about 110 ng*hr/mL, greater than about 120 ng*hr/mL, greater thanabout 130 ng*hr/mL, greater than about 140 ng*hr/mL, greater than about150 ng*hr/mL, greater than about 160 ng*hr/mL, greater than about 170ng*hr/mL, greater than about 180 ng*hr/mL, greater than about 190ng*hr/mL, greater than about 200 ng*hr/mL, greater than about 225ng*hr/mL, greater than about 250 ng*hr/mL, greater than about 275ng*hr/mL, greater than about 300 ng*hr/mL, greater than about 325ng*hr/mL, greater than about 350 ng*hr/mL, greater than about 375ng*hr/mL, greater than about 400 ng*hr/mL, greater than about 425ng*hr/mL, greater than about 450 ng*hr/mL, greater than about 475ng*hr/mL, greater than about 500 ng*hr/mL, greater than about 525ng*hr/mL, greater than about 550 ng*hr/mL, greater than about 575ng*hr/mL, greater than about 600 ng*hr/mL, greater than about 625ng*hr/mL, greater than about 650 ng*hr/mL, greater than about 675ng*hr/mL, greater than about 700 ng*hr/mL, greater than about 725ng*hr/mL, greater than about 750 ng*hr/mL, greater than about 775ng*hr/mL, greater than about 800 ng*hr/mL, greater than about 825ng*hr/mL, greater than about 850 ng*hr/mL, greater than about 875ng*hr/mL, greater than about 900 ng*hr/mL, greater than about 925ng*hr/mL, greater than about 950 ng*hr/mL, greater than about 975ng*hr/mL, or greater than about 1000 ng*hr/mL after administration ofthe formulation to the patient. In some embodiments of the methodsdisclosed herein, an inhalation formulation administered with aninhalation device, e.g., a high efficiency nebulizer, produces in ahuman subject group an average AUC_((0-∞)) of cromolyn sodium of about100 ng*hr/mL, about 110 ng*hr/mL, about 120 ng*hr/mL, about 130ng*hr/mL, about 140 ng*hr/mL, about 150 ng*hr/mL, about 160 ng*hr/mL,about 170 ng*hr/mL, about 180 ng*hr/mL, about 190 ng*hr/mL, about 200ng*hr/mL, about 225 ng*hr/mL, about 250 ng*hr/mL, about 275 ng*hr/mL,about 300 ng*hr/mL, about 325 ng*hr/mL, about 350 ng*hr/mL, about 375ng*hr/mL, about 400 ng*hr/mL, about 425 ng*hr/mL, about 450 ng*hr/mL,about 475 ng*hr/mL, about 500 ng*hr/mL, about 525 ng*hr/mL, about 550ng*hr/mL, about 575 ng*hr/mL, about 600 ng*hr/mL, about 625 ng*hr/mL,about 650 ng*hr/mL, about 675 ng*hr/mL, about 700 ng*hr/mL, about 725ng*hr/mL, about 750 ng*hr/mL, about 775 ng*hr/mL, about 800 ng*hr/mL,about 825 ng*hr/mL, about 850 ng*hr/mL, about 875 ng*hr/mL, about 900ng*hr/mL, about 925 ng*hr/mL, about 950 ng*hr/mL, about 975 ng*hr/mL, orabout 1000 ng*hr/mL after administration of the formulation to thepatient.

In some embodiments of the methods disclosed herein, an inhalationformulation administered with an inhalation device, e.g., a highefficiency nebulizer, produces in a human subject group an averageC_(max) of a mast cell stabilizer greater than about 40 ng/mL, greaterthan about 50 ng/mL, greater than about 60 ng/mL, greater than about 70ng/mL, greater than about 80 ng/mL, greater than about 90 ng/mL, greaterthan about 100 ng/mL, greater than about 110 ng/mL, greater than about120 ng/mL, greater than about 130 ng/mL, greater than about 140 ng/mL,greater than about 150 ng/mL, greater than about 160 ng/mL, greater thanabout 170 ng/mL, greater than about 180 ng/mL, greater than about 190ng/mL, greater than about 200 ng/mL, greater than about 210 ng/mL,greater than about 220 ng/mL, greater than about 230 ng/mL, greater thanabout 240 ng/mL, greater than about 250 ng/mL, greater than about 260ng/mL, greater than about 270 ng/mL, greater than about 280 ng/mL,greater than about 290 ng/mL, greater than about 300 ng/mL, greater thanabout 310 ng/mL, greater than about 320 ng/mL, greater than about 330ng/mL, greater than about 340 ng/mL, greater than about 350 ng/mL,greater than about 360 ng/mL, greater than about 370 ng/mL, greater thanabout 380 ng/mL, greater than about 390 ng/mL, or greater than about 400ng/mL after administration of the formulation to the patient. In someembodiments of the methods disclosed herein, an inhalation formulationadministered with an inhalation device, e.g., a high efficiencynebulizer, produces in a human subject group an average C_(max) of amast cell stabilizer of about 50 mg/mL, about 60 ng/mL, about 70 ng/mL,about 80 ng/mL, 90 ng/mL, about 100 ng/mL, about 110 ng/mL, about 120ng/mL, about 130 ng/mL, about 140 ng/mL, about 150 ng/mL, about 160ng/mL, about 170 ng/mL, about 180 ng/mL, about 190 ng/mL, about 200ng/mL, about 210 ng/mL, about 220 ng/mL, about 230 ng/mL, about 240ng/mL, about 250 ng/mL, 260 ng/mL, about 270 ng/mL, about 280 ng/mL,about 290 ng/mL, about 300 ng/mL, about 310 ng/mL, about 320 ng/mL,about 330 ng/mL, about 340 ng/mL, about 350 ng/mL, about 360 ng/mL,about 370 ng/mL, about 380 ng/mL, about 390 ng/mL, or about 400 ng/mLafter administration of the formulation to the patient.

In some embodiments of the methods disclosed herein, an inhalationformulation administered with an inhalation device, e.g., a highefficiency nebulizer, produces in a human subject group an averageC_(max) of cromolyn sodium greater than about 40 ng/mL, greater thanabout 50 ng/mL, greater than about 60 ng/mL, greater than about 70ng/mL, greater than about 80 ng/mL, greater than about 90 ng/mL, greaterthan about 100 ng/mL, greater than about 110 ng/mL, greater than about120 ng/mL, greater than about 130 ng/mL, greater than about 140 ng/mL,greater than about 150 ng/mL, greater than about 160 ng/mL, greater thanabout 170 ng/mL, greater than about 180 ng/mL, greater than about 190ng/mL, greater than about 200 ng/mL, greater than about 210 ng/mL,greater than about 220 ng/mL, greater than about 230 ng/mL, greater thanabout 240 ng/mL, greater than about 250 ng/mL, greater than about 260ng/mL, greater than about 270 ng/mL, greater than about 280 ng/mL,greater than about 290 ng/mL, greater than about 300 ng/mL, greater thanabout 310 ng/mL, greater than about 320 ng/mL, greater than about 330ng/mL, greater than about 340 ng/mL, greater than about 350 ng/mL,greater than about 360 ng/mL, greater than about 370 ng/mL, greater thanabout 380 ng/mL, greater than about 390 ng/mL, or greater than about 400ng/mL after administration of the formulation to the patient. In someembodiments of the methods disclosed herein, an inhalation formulationadministered with an inhalation device, e.g., a high efficiencynebulizer, produces in a human subject group an average C_(max) ofcromolyn sodium of about 50 mg/mL, about 60 ng/mL, about 70 ng/mL, about80 ng/mL, 90 ng/mL, about 100 ng/mL, about 110 ng/mL, about 120 ng/mL,about 130 ng/mL, about 140 ng/mL, about 150 ng/mL, about 160 ng/mL,about 170 ng/mL, about 180 ng/mL, about 190 ng/mL, about 200 ng/mL,about 210 ng/mL, about 220 ng/mL, about 230 ng/mL, about 240 ng/mL,about 250 ng/mL, 260 ng/mL, about 270 ng/mL, about 280 ng/mL, about 290ng/mL, about 300 ng/mL, about 310 ng/mL, about 320 ng/mL, about 330ng/mL, about 340 ng/mL, about 350 ng/mL, about 360 ng/mL, about 370ng/mL, about 380 ng/mL, about 390 ng/mL, or about 400 ng/mL afteradministration of the formulation to the patient.

In some embodiments of the methods disclosed herein, an inhalationformulation administered with an inhalation device, e.g., a highefficiency nebulizer, produces in a human subject group an averageAUC_((0-∞)) of a mast cell stabilizer greater than about 120 ng*hr/mLand/or an average C_(max) of the mast cell stabilizer greater than about55 ng/mL. In some embodiments of the methods disclosed herein, aninhalation formulation administered with an inhalation device, e.g., ahigh efficiency nebulizer, produces in a human subject group an averageAUC_((0-∞)) of a mast cell stabilizer greater than about 120 ng*hr/mLand an average C_(max) of the mast cell stabilizer greater than about 55ng/mL. In some embodiments of the methods disclosed herein, aninhalation formulation administered with an inhalation device, e.g., ahigh efficiency nebulizer, produces in a human subject group an averageAUC_((0-∞)) of a mast cell stabilizer greater than about 200 ng*hr/mLand an average C_(max) of the mast cell stabilizer greater than about 80ng/mL. In some embodiments of the methods disclosed herein, aninhalation formulation administered with an inhalation device, e.g., ahigh efficiency nebulizer, produces in a human subject group an averageAUC_((0-∞)) of a mast cell stabilizer greater than about 330 ng*hr/mLand an average C_(max) of the mast cell stabilizer greater than about150 ng/mL. In some embodiments, of the methods disclosed herein, aninhalation formulation administered with an inhalation device, e.g., ahigh efficiency nebulizer, produces in a human subject group an averageAUC_((0-∞)) of a mast cell stabilizer greater than about 525 ng*hr/mLand an average C_(max) of the mast cell stabilizer greater than about230 ng/mL.

In some embodiments of the methods disclosed herein, an inhalationformulation administered with an inhalation device, e.g., a highefficiency nebulizer, produces in a human subject group an averageAUC_((0-∞)) of cromolyn sodium greater than about 120 ng*hr/mL and/or anaverage C_(max) of cromolyn sodium greater than about 55 ng/mL. In someembodiments of the methods disclosed herein, an inhalation formulationadministered with an inhalation device, e.g., a high efficiencynebulizer, produces in a human subject group an average AUC_((0-∞)) ofcromolyn sodium greater than about 120 ng*hr/mL and an average C_(max)of cromolyn sodium greater than about 55 ng/mL. In some embodiments ofthe methods disclosed herein, an inhalation formulation administeredwith an inhalation device, e.g., a high efficiency nebulizer, producesin a human subject group an average AUC_((0-∞)) of cromolyn sodiumgreater than about 200 ng*hr/mL and an average C_(max) of cromolynsodium greater than about 80 ng/mL. In some embodiments of the methodsdisclosed herein, an inhalation formulation administered with aninhalation device, e.g., a high efficiency nebulizer, produces in ahuman subject group an average AUC_((0-∞)) of cromolyn sodium greaterthan about 330 ng*hr/mL and an average C_(max) of cromolyn sodiumgreater than about 150 ng/mL. In some embodiments, of the methodsdisclosed herein, an inhalation formulation administered with aninhalation device, e.g., a high efficiency nebulizer, produces in ahuman subject group an average AUC_((0-∞)) of cromolyn sodium greaterthan about 525 ng*hr/mL and an average C_(max) of cromolyn sodiumgreater than about 230 ng/mL.

In some embodiments of the methods disclosed herein, an inhalationformulation administered with an inhalation device, e.g., a highefficiency nebulizer, produces in a human subject group an averageAUC_((0-∞)) of cromolyn sodium of about 200 ng*hr/mL and an averageC_(max) of cromolyn sodium of about 80 ng/mL when a nominal dose of 40mg of cromolyn sodium is administered with the inhalation device. Insome embodiments of the methods disclosed herein, an inhalationformulation administered with an inhalation device, e.g., a highefficiency nebulizer, produces in a human subject group an averageAUC_((0-∞)) of cromolyn sodium of about 330 ng*hr/mL and an averageC_(max) of cromolyn sodium of about 150 ng/mL when a nominal dose of 40mg of cromolyn sodium is administered with the inhalation device. Insome embodiments of the methods disclosed herein, an inhalationformulation administered with an inhalation device, e.g., a highefficiency nebulizer, produces in a human subject group an averageAUC_((0-∞)) of cromolyn sodium of about 525 ng*hr/mL and an averageC_(max) of cromolyn sodium of about 230 ng/mL when a nominal dose of 80mg of cromolyn sodium is administered with the inhalation device.

In some embodiments of the methods disclosed herein, an inhalationformulation administered with an inhalation device, e.g., a highefficiency nebulizer, produces in a human subject group an averageAUC_((0-∞)) of cromolyn sodium of about 180 ng*hr/mL to about 220ng*hr/mL and an average C_(max) of cromolyn sodium of about 70 ng/mL toabout 90 ng/mL when a nominal dose of 40 mg of cromolyn sodium isadministered with the inhalation device. In some embodiments of themethods disclosed herein, an inhalation formulation administered with aninhalation device, e.g., a high efficiency nebulizer, produces in ahuman subject group an average AUC_((0-∞)) of cromolyn sodium of about300 ng*hr/mL to about 360 ng*hr/mL and an average C_(max) of cromolynsodium of about 135 ng/mL to about 165 ng/mL when a nominal dose of 40mg of cromolyn sodium is administered with the inhalation device. Insome embodiments, of the methods disclosed herein, an inhalationformulation administered with an inhalation device, e.g., a highefficiency nebulizer, produces in a human subject group an averageAUC_((0-∞)) of cromolyn sodium of about 475 ng*hr/mL to about 575ng*hr/mL and an average C_(max) of cromolyn sodium of about 200 ng/mL toabout 260 ng/mL when a nominal dose of 80 mg of cromolyn sodium isadministered with the inhalation device.

In some embodiments of the methods disclosed herein, an inhalationformulation administered with an inhalation device, e.g., a highefficiency nebulizer, provides mast cell stabilizer lung deposition(deposited lung dose) of at least about 15%, at least about 20%, atleast about 25%, at least about 30%, at least about 35%, at least about40%, at least about 45%, at least about 50%, at least about 55%, atleast about 60%, about 20% to about 40%, about 25% to about 35%, about25 to about 30%, about 25% to about 75%, about 30% to about 50%, about35% to about 90%, about 40% to about 80%, about 40% to about 60%, about50% to about 60%, about 50% to about 70%, or about 60% to about 75%based on the nominal dose of the mast cell stabilizer. In someembodiments of the methods disclosed herein, an inhalation formulationadministered with an inhalation device, e.g., a high efficiencynebulizer, provides cromolyn sodium deposition (deposited lung dose) ofat least about 15%, at least about 20%, at least about 25%, at leastabout 30%, at least about 35%, at least about 40%, at least about 45%,at least about 50%, at least about 55%, at least about 60%, about 20% toabout 40%, about 25% to about 35%, about 25 to about 30%, about 25% toabout 75%, about 30% to about 50%, about 35% to about 90%, about 40% toabout 80%, about 40% to about 60%, about 50% to about 60%, about 50% toabout 70%, or about 60% to about 75% based on the nominal dose of thecromolyn sodium.

In some embodiments of the methods disclosed herein, an inhalationformulation administered with an inhalation device, e.g., a highefficiency nebulizer, provides mast cell stabilizer lung deposition(deposited lung dose) of about 15%, about 20%, about 25%, about 30%,about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about65%, about 70%, about 75% about 80%, about 85%, about 90%, about 95%, orabout 100% based on the nominal dose of the mast cell stabilizer. Insome embodiments of the methods disclosed herein, an inhalationformulation administered with an inhalation device, e.g., a highefficiency nebulizer, provides cromolyn sodium lung deposition(deposited lung dose) of about 15%, about 20%, about 25%, about 30%,about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about65%, about 70%, about 75% about 80%, about 85%, about 90%, about 95%, orabout 100% based on the nominal dose of the cromolyn sodium.

In some embodiments of the methods disclosed herein, an inhalationformulation administered with an inhalation device, e.g., a highefficiency nebulizer, provides mast cell stabilizer lung deposition(deposited lung dose) of greater than about 0.5 mg, greater than about 1mg, greater than about 1.5 mg, greater than about 2 mg, greater thanabout 2.5 mg, greater than about 3 mg, greater than about 3.5 mg,greater than about 4 mg, greater than about 5 mg, greater than about 6mg, greater than about 7 mg, greater than about 8 mg, greater than about9 mg, greater than about 10 mg, greater than about 11 mg, greater thanabout 12 mg, greater than about 13 mg, greater than about 14 mg, orgreater than about 15 mg. In some embodiments of the methods disclosedherein, an inhalation formulation administered with an inhalationdevice, e.g., a high efficiency nebulizer, provides mast cell stabilizerlung deposition (deposited lung dose) of about 0.5 mg, about 1.0 mg,about 1.5 mg, about 2.0 mg, about 2.5 mg, about 3.0 mg, about 3.5 mg,about 4.0 mg, about 5.0 mg, about 6.0 mg, about 7.0 mg, about 8.0 mg,about 9.0 mg, about 10 mg, about 11 mg, about 12 mg, about 13 mg, about14 mg, or about 15 mg.

In some embodiments of the methods disclosed herein, an inhalationformulation administered with an inhalation device, e.g., a highefficiency nebulizer, provides cromolyn sodium lung deposition(deposited lung dose) of greater than about 0.5 mg, greater than about 1mg, greater than about 1.5 mg, greater than about 2 mg, greater thanabout 2.5 mg, greater than about 3 mg, greater than about 3.5 mg,greater than about 4 mg, greater than about 5 mg, greater than about 6mg, greater than about 7 mg, greater than about 8 mg, greater than about9 mg, greater than about 10 mg, greater than about 11 mg, greater thanabout 12 mg, greater than about 13 mg, greater than about 14 mg, orgreater than about 15 mg. In some embodiments of the methods disclosedherein, an inhalation formulation administered with an inhalationdevice, e.g., a high efficiency nebulizer, provides cromolyn sodium lungdeposition (deposited lung dose) of about 0.5 mg, about 1.0 mg, about1.5 mg, about 2.0 mg, about 2.5 mg, about 3.0 mg, about 3.5 mg, about4.0 mg, about 5.0 mg, about 6.0 mg, about 7.0 mg, about 8.0 mg, about9.0 mg, about 10 mg, about 11 mg, about 12 mg, about 13 mg, about 14 mg,or about 15 mg.

In some embodiments of the methods disclosed herein, an inhalationformulation containing a mast cell stabilizer is administered with aninhalation device, e.g., a high efficiency nebulizer, at anadministration of less than about 1 mg/dose, about 1 mg/dose to about100 mg/dose, about 5 mg/dose to about 80 mg/dose, about 20 mg/dose toabout 60 mg/dose, about 30 mg/dose to about 50 mg/dose, or greater than100 mg/dose. In some embodiments of the methods disclosed herein, aninhalation formulation containing cromolyn sodium is administered withan inhalation device, e.g., a high efficiency nebulizer, at anadministration of less than about 1 mg/dose, about 1 mg/dose to about100 mg/dose, about 5 mg/dose to about 80 mg/dose, about 20 mg/dose toabout 60 mg/dose, about 30 mg/dose to about 50 mg/dose, or greater than100 mg/dose. In some embodiments of the methods disclosed herein, a mastcell stabilizer is administered in an inhalation formulation with aninhalation device, e.g., a high efficiency nebulizer, in about 1 mg,about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg,about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about85 mg, about 90 mg, about 95 mg, about 100 mg, about 105 mg, about 110mg, about 115 mg, about 120 mg, about 125 mg, about 130 mg doses, about135 mg, about 140 mg, about 145 mg, about 150 mg, about 200 mg, about250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about500 mg, about 550 mg, about 600 mg, about 650 mg, about 700 mg, about750 mg, about 800 mg, about 850 mg, about 900 mg, about 950 mg, or about1000 mg doses. In some embodiments of the methods disclosed herein,cromolyn sodium is administered in an inhalation formulation with aninhalation device, e.g., a high efficiency nebulizer, in about 1 mg,about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg,about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about85 mg, about 90 mg, about 95 mg, about 100 mg, about 105 mg, about 110mg, about 115 mg, about 120 mg, about 125 mg, about 130 mg doses, about135 mg, about 140 mg, about 145 mg, about 150 mg, about 200 mg, about250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about500 mg, about 550 mg, about 600 mg, about 650 mg, about 700 mg, about750 mg, about 800 mg, about 850 mg, about 900 mg, about 950 mg, or about1000 mg doses.

In some embodiments of the methods disclosed herein, an inhalationformulation administered with an inhalation device, e.g., a highefficiency nebulizer provides a bioavailability of a mast cellstabilizer of greater than about 5%, greater than about 6%, greater thanabout 7%, greater than about 8%, greater than about 9%, greater thanabout 10%, greater than about 11%, greater than about 12%, greater thanabout 13%, greater than about 14%, greater than about 15%, greater thanabout 16%, greater than about 17%, greater than about 18%, greater thanabout 19%, greater than about 20%, greater than about 25%, greater thanabout 30%, greater than about 35%, greater than about 40%, greater thanabout 45%, greater than about 50%, greater than about 55%, or greaterthan about 60% of the nominal dose. In some embodiments, an inhalationformulation administered with an inhalation device, e.g., a highefficiency nebulizer, in the methods disclosed herein provides abioavailability of a mast cell stabilizer of about 5%, about 6%, about7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%,about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, about20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%,about 55%, or about 60% of the nominal dose.

In some embodiments of the methods disclosed herein, an inhalationformulation administered with an inhalation device, e.g., a highefficiency nebulizer provides a bioavailability of cromolyn sodium ofgreater than about 5%, greater than about 6%, greater than about 7%,greater than about 8%, greater than about 9%, greater than about 10%,greater than about 11%, greater than about 12%, greater than about 13%,greater than about 14%, greater than about 15%, greater than about 16%,greater than about 17%, greater than about 18%, greater than about 19%,greater than about 20%, greater than about 25%, greater than about 30%,greater than about 35%, greater than about 40%, greater than about 45%,or greater than about 50% of the nominal dose. In some embodiments, anaqueous inhalation formulation administered with an inhalation device,e.g., a high efficiency nebulizer, in the methods disclosed hereinprovides a bioavailability of cromolyn sodium of about 5%, about 6%,about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%,about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, orabout 50% of the nominal dose.

In some embodiments of the methods disclosed herein, an inhalationformulation administered with an inhalation device, e.g., a highefficiency nebulizer, provides a bioavailability of a mast cellstabilizer greater than about 5% and produces in a human subject groupan average AUC_((0-∞)) of the mast cell stabilizer greater than about120 ng*hr/mL and/or an average C_(max) of the mast cell stabilizergreater than about 55 ng/mL. In some embodiments of the methodsdisclosed herein, an inhalation formulation administered with aninhalation device, e.g., a high efficiency nebulizer, provides abioavailability of a mast cell stabilizer greater than about 5% andproduces in a human subject group an average AUC_((0-∞)) of the mastcell stabilizer greater than about 120 ng*hr/mL and an average C_(max)of the mast cell stabilizer greater than about 55 ng/mL. In someembodiments of the methods disclosed herein, an inhalation formulationadministered with an inhalation device, e.g., a high efficiencynebulizer, provides a bioavailability of a mast cell stabilizer greaterthan about 5% and produces in a human subject group an averageAUC_((0-∞)) of the mast cell stabilizer greater than about 200 ng*hr/mLand an average C_(max) of the mast cell stabilizer greater than about 80ng/mL. In some embodiments of the methods disclosed herein, aninhalation formulation administered with an inhalation device, e.g., ahigh efficiency nebulizer, provides a bioavailability of a mast cellstabilizer greater than about 5% and produces in a human subject groupan average AUC_((0-∞)) of the mast cell stabilizer greater than about330 ng*hr/mL and an average C_(max) of the mast cell stabilizer greaterthan about 150 ng/mL. In some embodiments, of the methods disclosedherein, an inhalation formulation administered with an inhalationdevice, e.g., a high efficiency nebulizer, provides a bioavailability ofa mast cell stabilizer greater than about 5% and produces in a humansubject group an average AUC_((0-∞)) of the mast cell stabilizer greaterthan about 525 ng*hr/mL and an average C_(max) of the mast cellstabilizer greater than about 230 ng/mL.

In some embodiments of the methods disclosed herein, an inhalationformulation administered with an inhalation device, e.g., a highefficiency nebulizer, provides a bioavailability of cromolyn sodiumgreater than about 5% and produces in a human subject group an averageAUC_((0-∞)) of cromolyn sodium greater than about 120 ng*hr/mL and/or anaverage C_(max) of cromolyn sodium greater than about 55 ng/mL. In someembodiments of the methods disclosed herein, an inhalation formulationadministered with an inhalation device, e.g., a high efficiencynebulizer, provides a bioavailability of cromolyn sodium greater thanabout 5% and produces in a human subject group an average AUC_((0-∞)) ofcromolyn sodium greater than about 120 ng*hr/mL and an average C_(max)of cromolyn sodium greater than about 55 ng/mL. In some embodiments ofthe methods disclosed herein, an inhalation formulation administeredwith an inhalation device, e.g., a high efficiency nebulizer, provides abioavailability of cromolyn sodium greater than about 5% and produces ina human subject group an average AUC_((0-∞)) of cromolyn sodium greaterthan about 200 ng*hr/mL and an average C_(max) of cromolyn sodiumgreater than about 80 ng/mL. In some embodiments of the methodsdisclosed herein, an inhalation formulation administered with aninhalation device, e.g., a high efficiency nebulizer, provides abioavailability of cromolyn sodium greater than about 5% and produces ina human subject group an average AUC_((0-∞)) of cromolyn sodium greaterthan about 330 ng*hr/mL and an average C_(max) of cromolyn sodiumgreater than about 150 ng/mL. In some embodiments, of the methodsdisclosed herein, an inhalation formulation administered with aninhalation device, e.g., a high efficiency nebulizer, provides abioavailability of cromolyn sodium greater than about 5% and produces ina human subject group an average AUC_((0-∞)) of cromolyn sodium greaterthan about 525 ng*hr/mL and an average C_(max) of cromolyn sodiumgreater than about 230 ng/mL.

In some embodiments of the methods disclosed herein, an inhalationformulation administered with an inhalation device, e.g., a highefficiency nebulizer, provides a bioavailability of a mast cellstabilizer greater than about 5% and produces in a human subject groupan average AUC_((0-∞)) of a mast cell stabilizer greater than about 120ng*hr/mL. In some embodiments of the methods disclosed herein, aninhalation formulation administered with an inhalation device, e.g., ahigh efficiency nebulizer, provides a bioavailability of a mast cellstabilizer greater than about 5% and produces in a human subject groupan average AUC_((0-∞)) of a mast cell stabilizer greater than about 200ng*hr/mL. In some embodiments of the methods disclosed herein, aninhalation formulation administered with an inhalation device, e.g., ahigh efficiency nebulizer, provides a bioavailability of a mast cellstabilizer greater than about 5% and produces in a human subject groupan average AUC_((0-∞)) of a mast cell stabilizer greater than about 330ng*hr/mL. In some embodiments of the methods disclosed herein, aninhalation formulation administered with an inhalation device, e.g., ahigh efficiency nebulizer, provides a bioavailability of a mast cellstabilizer greater than about 5% and produces in a human subject groupan average AUC_((0-∞)) of a mast cell stabilizer greater than about 525ng*hr/mL.

In some embodiments of the methods disclosed herein, an inhalationformulation administered with an inhalation device, e.g., a highefficiency nebulizer, provides a bioavailability of cromolyn sodiumgreater than about 5% and produces in a human subject group an averageAUC_((0-∞)) of cromolyn sodium greater than about 120 ng*hr/mL. In someembodiments of the methods disclosed herein, an inhalation formulationadministered with an inhalation device, e.g., a high efficiencynebulizer, provides a bioavailability of cromolyn sodium greater thanabout 5% and produces in a human subject group an average AUC_((0-∞)) ofcromolyn sodium greater than about 200 ng*hr/mL. In some embodiments ofthe methods disclosed herein, an inhalation formulation administeredwith an inhalation device, e.g., a high efficiency nebulizer, provides abioavailability of cromolyn sodium greater than about 5% and produces ina human subject group an average AUC_((0-∞)) of cromolyn sodium greaterthan about 330 ng*hr/mL. In some embodiments, of the methods disclosedherein, an inhalation formulation administered with an inhalationdevice, e.g., a high efficiency nebulizer, provides a bioavailability ofcromolyn sodium greater than about 5% and produces in a human subjectgroup an average AUC_((0-∞)) of cromolyn sodium greater than about 525ng*hr/mL.

In some embodiments of the methods disclosed herein, an inhalationformulation comprising 40 mg cromolyn sodium administered with aninhalation device, e.g., a high efficiency nebulizer, provides abioavailability of cromolyn sodium greater than about 5% and produces ina human subject group an average AUC_((0-∞)) of cromolyn sodium greaterthan about 200 ng*hr/mL. In some embodiments of the methods disclosedherein, an inhalation formulation comprising 40 mg cromolyn sodiumadministered with an inhalation device, e.g., a high efficiencynebulizer, provides a bioavailability of cromolyn sodium greater thanabout 5% and produces in a human subject group an average AUC_((0-∞)) ofcromolyn sodium greater than about 330 ng*hr/mL. In some embodiments, ofthe methods disclosed herein, an inhalation formulation comprising 80 mgcromolyn sodium administered with an inhalation device, e.g., a highefficiency nebulizer, provides a bioavailability of cromolyn sodiumgreater than about 5% and produces in a human subject group an averageAUC_((0-∞)) of cromolyn sodium greater than about 525 ng*hr/mL.

In some embodiments of the methods disclosed herein, an inhalationformulation administered with an inhalation device, e.g., a highefficiency nebulizer, has an RF (≤3.3 μm) of at least about 30% andproduces in a human subject group an average AUC_((0-∞)) of a mast cellstabilizer greater than about 120 ng*hr/mL. In some embodiments of themethods disclosed herein, an inhalation formulation administered with aninhalation device, e.g., a high efficiency nebulizer, has an RF (≤3.3μm) of at least about 30% and produces in a human subject group anaverage AUC_((0-∞)) of a mast cell stabilizer greater than about 200ng*hr/mL. In some embodiments of the methods disclosed herein, aninhalation formulation administered with an inhalation device, e.g., ahigh efficiency nebulizer, has an RF (≤3.3 μm) of at least about 40% andproduces in a human subject group an average AUC_((0-∞)) of a mast cellstabilizer greater than about 330 ng*hr/mL. In some embodiments, of themethods disclosed herein, an inhalation formulation administered with aninhalation device, e.g., a high efficiency nebulizer, has an RF (≤3.3μm) of at least about 40% and produces in a human subject group anaverage AUC_((0-∞)) of a mast cell stabilizer greater than about 525ng*hr/mL.

In some embodiments of the methods disclosed herein, an inhalationformulation administered with an inhalation device, e.g., a highefficiency nebulizer, has an RF (≤3.3 μm) of at least about 30% andproduces in a human subject group an average AUC_((0-∞)) of cromolynsodium greater than about 120 ng*hr/mL. In some embodiments of themethods disclosed herein, an inhalation formulation administered with aninhalation device, e.g., a high efficiency nebulizer, has an RF (≤3.3μm) of at least about 30% and produces in a human subject group anaverage AUC_((0-∞)) of cromolyn sodium greater than about 200 ng*hr/mL.In some embodiments of the methods disclosed herein, an inhalationformulation administered with an inhalation device, e.g., a highefficiency nebulizer, has an RF (≤3.3 μm) of at least about 40% andproduces in a human subject group an average AUC_((0-∞)) of cromolynsodium greater than about 330 ng*hr/mL. In some embodiments, of themethods disclosed herein, an inhalation formulation administered with aninhalation device, e.g., a high efficiency nebulizer, has an RF (≤3.3μm) of at least about 40% and produces in a human subject group anaverage AUC_((0-∞)) of cromolyn sodium greater than about 525 ng*hr/mL.

In some embodiments of the methods disclosed herein, an inhalationformulation comprising 40 mg cromolyn sodium administered with aninhalation device, e.g., a high efficiency nebulizer, has an RF (≤3.3μm) of at least about 30% and produces in a human subject group anaverage AUC_((0-∞)) of cromolyn sodium greater than about 200 ng*hr/mL.In some embodiments of the methods disclosed herein, an inhalationformulation comprising 40 mg cromolyn sodium administered with aninhalation device, e.g., a high efficiency nebulizer, has an RF (≤3.3μm) of at least about 40% and produces in a human subject group anaverage AUC_((0-∞)) of cromolyn sodium greater than about 330 ng*hr/mL.In some embodiments of the methods disclosed herein, an inhalationformulation comprising 80 mg cromolyn sodium administered with aninhalation device, e.g., a high efficiency nebulizer, has an RF (≤3.3μm) of at least about 40% and produces in a human subject group anaverage AUC_((0-∞)) of cromolyn sodium greater than about 525 ng*hr/mL.

In some embodiments of the methods disclosed herein, an inhalationformulation administered with an inhalation device, e.g., a highefficiency nebulizer, produces in a human subject group an averageAUC_((0-∞)) of cromolyn sodium of about 8.5 ng*hr/mL and an averageC_(max) of cromolyn sodium of about 3.9 ng/mL per mg of cromolyn sodiumadministered with the inhalation device. In some embodiments of themethods disclosed herein, an inhalation formulation administered with aninhalation device, e.g., a high efficiency nebulizer, produces in ahuman subject group an average AUC_((0-∞)) of cromolyn sodium of about6.6 ng*hr/mL and an average C_(max) of cromolyn sodium of about 3.0ng/mL per mg of cromolyn sodium administered with the inhalation device.In some embodiments of the methods disclosed herein, an inhalationformulation administered with an inhalation device, e.g., a highefficiency nebulizer, produces in a human subject group an averageAUC_((0-∞)) of cromolyn sodium of about 5.3 ng*hr/mL and an averageC_(max) of cromolyn sodium of about 2.2 ng/mL per mg of cromolyn sodiumadministered with the inhalation device. In some embodiments of themethods disclosed herein, an inhalation formulation administered with aninhalation device, e.g., a high efficiency nebulizer, produces in ahuman subject group an average AUC_((0-∞)) of cromolyn sodium of fromabout 5.3 ng*hr/mL to about 8.5 ng*hr/mL and an average C_(max) ofcromolyn sodium of about 2.2 ng/mL to about 3.9 ng/mL per mg of cromolynsodium administered with the inhalation device when the nominal dose ofcromolyn sodium administered is in the range of about 40 mg to about 80mg.

In some embodiments of the methods disclosed herein, an inhalationformulation containing a mast cell stabilizer such as cromolyn sodium isadministered with an inhalation device, e.g., a high efficiencynebulizer, at a fill volume of less than about 0.25 mL, less than about0.5 mL, at least about 0.5 mL to about 1.5 mL, at least about 0.5 mL toabout 1.8 mL, at least about 1.5 mL, or at least about 2.0 mL. In someembodiments, an inhalation formulation is administered with aninhalation device, e.g., a high efficiency nebulizer, at a fill volumeabout 0.1 mL to about 5.0 mL, about 0.25 mL to about 2.0 mL, about 0.5mL to about 1.8 mL, about 0.5 mL to about 2 mL, about 0.5 mL to about1.5 mL, about 0.5 mL to about 1.0 mL, about 0.5 mL or less, about 1 mLor less, about 1.5 mL or less, about 2.0 mL or less, about 2.5 mL orless, about 3.0 mL or less, about 3.5 mL or less, about 4.0 mL or less,about 4.5 mL or less, or about 5.0 mL or less. In some embodiments, aninhalation formulation is administered with an inhalation device, e.g.,a high efficiency nebulizer, at a fill volume of about 0.5 mL, about 1.0mL, about 1.5 mL, about 1.8 mL, about 2.0 mL, about 2.5 mL, about 3.0mL, about 3.5 mL, about 4.0 mL, about 4.5 mL, or about 5.0 mL. In someembodiments, an inhalation formulation is administered with aninhalation device, e.g., a high efficiency nebulizer, which provides fora residual volume of mast cell stabilizer after administration of themast cell stabilizer of less than about 10%, less than about 5%, or lessthan about 3% of the nominal dose.

In some embodiments of the methods disclosed herein, an inhalationformulation containing a mast cell stabilizer is administered with aninhalation device, e.g., a high efficiency nebulizer, wherein theconcentration of the mast cell stabilizer is greater than about 1% byweight, greater than about 2% by weight, greater than about 3% byweight, greater than about 4% by weight, greater than about 5% byweight, greater than about 6% by weight, greater than about 7% byweight, greater than about 8% by weight, greater than about 9% byweight, or greater than about 10% by weight. In some embodiments of themethods disclosed herein, an inhalation formulation containing a mastcell stabilizer is administered with an inhalation device, e.g., a highefficiency nebulizer, wherein the concentration of the mast cellstabilizer is from about 1% by weight to about 10% by weight, from about2% by weight to about 8% by weight, from about 2% by weight to about 6%by weight, or from about 3% by weight to about 5% by weight. In someembodiments of the methods disclosed herein, an inhalation formulationcontaining a mast cell stabilizer is administered with an inhalationdevice, e.g., a high efficiency nebulizer, wherein the concentration ofthe mast cell stabilizer is about 1% by weight, about 2% by weight,about 3% by weight, about 4% by weight, about 5% by weight, about 6% byweight, about 7% by weight, about 8% by weight, about 9% by weight, orabout 10% by weight.

In some embodiments of the methods disclosed herein, an inhalationformulation containing cromolyn sodium is administered with aninhalation device, e.g., a high efficiency nebulizer, wherein theconcentration of the cromolyn sodium is greater than about 1% by weight,greater than about 2% by weight, greater than about 3% by weight,greater than about 4% by weight, greater than about 5% by weight,greater than about 6% by weight, greater than about 7% by weight,greater than about 8% by weight, greater than about 9% by weight, orgreater than about 10% by weight. In some embodiments of the methodsdisclosed herein, an inhalation formulation containing cromolyn sodiumis administered with an inhalation device, e.g., a high efficiencynebulizer, wherein the concentration of the cromolyn sodium is fromabout 1% by weight to about 10% by weight, from about 2% by weight toabout 8% by weight, from about 2% by weight to about 6% by weight, orfrom about 3% by weight to about 5% by weight. In some embodiments ofthe methods disclosed herein, an inhalation formulation containingcromolyn sodium is administered with an inhalation device, e.g., a highefficiency nebulizer, wherein the concentration of the cromolyn sodiumis about 1% by weight, about 2% by weight, about 3% by weight, about 4%by weight, about 5% by weight, about 6% by weight, about 7% by weight,about 8% by weight, about 9% by weight, or about 10% by weight.

In some embodiments, an inhalation formulation containing a mast cellstabilizer is administered with an inhalation device, e.g., a highefficiency nebulizer, in about 0.25 to about 10 minutes, about 0.50 toabout 8 minutes, less than about 8 minutes, less than about 7 minutes,less than about 6 minutes, less than about 5 minutes, less than about 4minutes, less than about 3 minutes, less than about 2 minutes, less thanabout 1.8 minutes, less than about 1.5 minutes, or less than 1 minute.In some embodiments, the inhalation formulation is administered in about3 minutes or less. In some embodiments, the inhalation formulation isadministered in about 1 minute, about 2 minutes, about 3 minutes, about4 minutes, about 5 minutes, about 6 minutes, about 7 minutes, about 8minutes, about 9 minutes, or about 10 minutes.

In some embodiments of the methods disclosed herein, administration of amast cell stabilizer with a high efficiency nebulizer provides at leastabout a 1.5-fold, at least about a 1.8-fold, at least about a two-fold,at least about a three-fold, at least about a four-fold, or at leastabout a five-fold increase in one or more of AUC_(last), AUC_((0-∞)), orC_(max) as compared to the same or lower nominal dose of the mast cellstabilizer administered with a conventional inhalation device or an oralformulation, e.g., a liquid oral formulation, tablet, or capsule.

In some embodiments of the methods disclosed herein, inhalationformulations administered with a high efficiency nebulizer aresubstantially free of a preservative, such as benzyl alcohol. In someembodiments of the methods disclosed herein, inhalation formulationsadministered with a high efficiency nebulizer further comprise at leastone excipient. In some embodiments, the excipient is selected from thegroup consisting of stabilizers and antioxidants (such as citric acid,ascorbic acid, ethylenediamine tetra acetic acid (EDTA), sodiummetabisulfite, or a salt of any thereof), an osmolarity adjusting agent(such as sodium chloride, mannitol, or sorbitol), a surfactant (such aspolysorbate 80, vitamin E, tocopherol polyethylene glycol, andTyloxapol), or a pH buffer.

In some embodiments of the methods disclosed herein, inhalationformulations administered with an inhalation device, e.g., a highefficiency nebulizer, are hypotonic. In some embodiments of the methodsdisclosed herein, inhalation formulations administered with aninhalation device, e.g., a high efficiency nebulizer, are sub-isotonic.In some embodiments of the methods disclosed herein, inhalationformulations administered with an inhalation device, e.g., a highefficiency nebulizer, have an osmolality greater than about 70 mOsm/kg.In some embodiments of the methods disclosed herein, inhalationformulations administered with an inhalation device, e.g., highefficiency nebulizer, have an osmolality of at least about 100 mOsm/kg.In some embodiments of the methods disclosed herein, inhalationformulations administered with an inhalation device, e.g., highefficiency nebulizer, have an osmolality of at least about 150 mOsm/kg.

Combination Therapies

In some embodiments of the methods disclosed herein, one or moredifferent formulations of mast cell stabilizers are co-administered bydifferent routes of administration to provide systemically effectiveamounts of the mast cell stabilizers. For example, in some embodiments,a composition comprising a mast cell stabilizer, e.g., cromolyn sodium,is administered with a dry powder inhaler and a different compositioncomprising a mast cell stabilizer, e.g., cromolyn sodium, isco-administered in a liquid oral formulation to treat a systemic mastcell related disorder. In some embodiments, a composition comprising amast cell stabilizer, e.g., cromolyn sodium, is administered with a drypowder inhaler and a different composition comprising a mast cellstabilizer, e.g., cromolyn sodium, is co-administered in a solid oralformulation, e.g., a capsule or tablet, to treat a systemic mast cellrelated disorder. In some embodiments, a composition comprising a mastcell stabilizer, e.g., cromolyn sodium, is administered with a metereddose inhaler and a different composition comprising a mast cellstabilizer, e.g., cromolyn sodium, is co-administered in a liquid oralformulation to treat a systemic mast cell related disorder. In someembodiments, a composition comprising a mast cell stabilizer, e.g.,cromolyn sodium, is administered with a metered dose inhaler and adifferent composition comprising a mast cell stabilizer, e.g., cromolynsodium, is co-administered in a solid oral formulation, e.g., a tabletor capsule, to treat a systemic mast cell related disorder. In someembodiments, a composition comprising a mast cell stabilizer, e.g.,cromolyn sodium, is administered with a dry powder inhaler and adifferent composition comprising a mast cell stabilizer, e.g., cromolynsodium, is co-administered with a metered dose inhaler to treat asystemic mast cell related disorder. In some embodiments, a compositioncomprising a mast cell stabilizer, e.g., cromolyn sodium, isadministered with a dry powder inhaler and a different compositioncomprising a mast cell stabilizer, e.g., cromolyn sodium, isco-administered with a metered dose inhaler to treat a systemic mastcell related disorder. In some embodiments, a composition comprising amast cell stabilizer, e.g., cromolyn sodium, is administered with a highefficiency nebulizer and a different composition comprising a mast cellstabilizer, e.g., cromolyn sodium, is co-administered in a liquid oralformulation to treat a systemic mast cell related disorder. In someembodiments, a composition comprising a mast cell stabilizer, e.g.,cromolyn sodium, is administered with a high efficiency nebulizer and adifferent composition comprising a mast cell stabilizer, e.g., cromolynsodium, is co-administered in a solid oral formulation, e.g., a tabletor capsule, to treat a systemic mast cell related disorder. In someembodiments, a composition comprising a mast cell stabilizer, e.g.,cromolyn sodium, is administered with a jet nebulizer and a differentcomposition comprising a mast cell stabilizer, e.g., cromolyn sodium, isco-administered in a liquid oral formulation to treat a systemic mastcell related disorder. In some embodiments, a composition comprising amast cell stabilizer, e.g., cromolyn sodium, is administered with a jetnebulizer and a different composition comprising a mast cell stabilizer,e.g., cromolyn sodium, is co-administered in a solid oral formulation,e.g., a tablet or capsule, to treat a systemic mast cell relateddisorder.

EXAMPLES

The examples below describe some embodiments of the methods describedherein. Methods and materials that are not specifically described in thefollowing examples are within the scope of the invention and will beapparent to those skilled in the art with reference to the disclosureherein.

Example 1: Formulations

The formulations described in Table 1 are prepared as follows: Thecomposition ingredients are added sequentially to a glass beaker with amagnet stirrer and about 90 g of purified water in the order listed inTable 1, ensuring that each ingredient is dissolved before the next isadded. The weight is then adjusted to 100.0 g by adding additionalpurified water. The resulting solutions are then sterilized byfiltration through 0.2-0.22 μm sterile filters, and 0.5 to 5 mL aliquotsare added to pre-sterilized glass or sterile polyethylene orpolypropylene blow fill and seal vials by a standard blow fill and sealprocedure. Alternative sterilization methods may be applied using heatsterilization in an autoclave.

TABLE 1 Formulation No. 1 2 3 4 5 6 7 8 9 10 11 12 13 Cromolyn sodium(DSCG) (wt %) 2.0 3.0 4.0 4.0 4.0 4.0 4.0 5.0 6.0 3.0 3.0 3.0 3.0 NaCl(wt %) 0.7 0.5 0.3 0.25 0.2 0.2 0.2 0.15 0.1 0.2 0.3 0.4 0.5 Mannitol(wt %) 0.4 0.8 1.0 1.1 1.2 1.25 1.25 1.4 1.5 EDTA-Na (wt %) 0.01 0.020.03 0.01 0.02 0.03 0.02 0.03 0.04 0.01 0.02 0.03 0.04 Hyaluronic acid(wt %) 0.25 0.5 1.0 0.25 0.5 1.0 Propylene glycol (wt %) 1.0 2.0 3.0 4.0Purified Water (wt %) 96.9 95.7 94.4 94.1 93.6 94.5 94.5 93.4 92.4 95.894.4 93.1 91.5

Example 2: Characterization of Aerosols Produced with a High EfficiencyNebulizer

The MMAD, GSD, DD, and RF of a representative inhaled cromolyn sodiumformulation (PA-101) delivered via a high efficiency nebulizer (eFlow®,PARI, 30 L) were determined as described in USP<1601>. The valuesdetermined were: MMAD=3.5 μm; GSD=1.7; DD=68%; RF (≤5 μm)=75%; and RF(≤3.3 μm)=44%.

The MMAD, GSD, and RF of a representative inhaled cromolyn sodiumformulation (PA-101) delivered via a high efficiency nebulizer (eFlow®,PARI, 40 L) were determined as described in USP<1601>. The valuesdetermined were: MMAD=4.1 μm; GSD=1.7; RF (≤5 μm)=66%; and RF (≤3.3μm)=36%.

Example 3: Single-Dose, Dose Escalation Study

Objectives:

The objectives of the study are as follows:

Primary:

Part 1: To determine the systemic availability and pharmacokinetic (PK)profile of single doses of a representative inhaled cromolyn sodiumformulation (PA-101) delivered via a high efficiency nebulizer (eFlow®,PARI) using two different aerosol membranes (30 L and 40 L) incomparison with marketed formulations of cromolyn sodium (oral solutionand an inhalation aerosol) in healthy subjects.

Part 2: To assess the pharmacokinetic profile of PA-101 administered assingle day three times daily dosing via a high efficiency nebulizer(eFlow®, PARI) in comparison with marketed formulations of cromolynsodium (oral solution and inhalation aerosol) administered as single dayTID dosing in patients with systemic mastocytosis.

Secondary:

To assess the safety and tolerability of PA-101 in comparison withmarketed formulations of cromolyn sodium (oral solution and aninhalation aerosol).

Methodology:

This was a Phase 1, randomized, open-label, single-centre, dose-ranging,cross-over study conducted in two parts in total of 18 subjects. Part 1was conducted in total of 12 healthy adult subjects of 18-45 years ofage. Part 2 was conducted in a total of 5 adult patients of 18-45 yearsof age with systemic mastocytosis. Parts 1 and 2 were conducted inparallel.

Study Treatments, Dose and Mode of Administration:

Part 1:

-   -   1. 40 mg PA-101 (4% DSCG, 40 mg/1 mL), oral inhalation via eFlow        30 L.    -   2. 80 mg PA-101 (4% DSCG, 80 mg/2 mL), oral inhalation via eFlow        30 L.    -   3. 40 mg PA-101 (4% DSCG, 40 mg/1 mL), oral inhalation via eFlow        40 L.    -   4. 20 mg cromolyn sodium inhalation aerosol (1% DSCG, 20 mg/2        mL) (commercially available product), oral inhalation via LC        Plus.    -   5. 200 mg oral sodium cromoglycate solution (commercially        available product), oral administration.        Part 2:    -   1. 40 mg PA-101 (4% DSCG 40 mg/1 mL), oral inhalation via eFlow        30 L    -   2. 200 mg oral sodium cromoglycate solution (commercially        available product), oral administration.

In Part 1, all study subjects received each study treatment in themorning (at 8:00 am, +/−30 minutes) as a single dose treatment. Prior toeach dosing day, subjects were admitted to the clinic in the morning forbaseline (pre-dose) assessments. Subjects were required to remain in theclinic for 12 h after study drug administration on each dosing day.Treatment Visits were separated by a washout period of 2 to 5 days.

In Part 2, all study subjects received each study treatment three timesdaily (TID) (at 08:00 am, 14:00 μm and 20:00 μm, +/−30 minutes) as asingle day treatment. Prior to each dosing day, subjects were admittedto the clinic in the morning for baseline (pre-dose) assessments.Subjects were required to remain in the clinic for 24 h after study drugadministration on each dosing day.

The main delivery device for administering PA-101 was the open systemeFlow nebulizer using the 30 L aerosol head, which generates aerosolparticles with a median size of about 3.0 μm. The 40 L aerosol head(generating aerosol particles with a median size of about 4.0 μm) wastested as a comparator arm in Part 1 only.

Duration of Study:

The duration of both Parts 1 and 2 of the study was one day.

Criteria for Evaluation:

Pharmacokinetic measurements: The PK parameters evaluated for plasmacromolyn sodium (DSCG) were maximum concentration (C_(max)), time tomaximum concentration (T_(max)), terminal elimination half-life(T_(1/2)), area under the plasma concentration-time curve from time=0 totime of last measurable drug concentration AUC_((0-t)), and area underthe plasma concentration-time curve from time=0 to infinity AUC_((0-∞)).Urine DSCG levels were measured for total DSCG excretion in the urine,and the bioavailability of the DSCG was calculated from the measuredlevels.

Safety measurements: Adverse events including gastrointestinaldisturbance (e.g., abdominal pain, nausea, vomiting), changes in vitalsigns, 12-lead ECG and clinical laboratory tests (hematology, chemistryand urinalysis).

Statistical Measurements:

Pharmacokinetic parameters and plasma concentrations are listed andsummarized. The summary statistics are presented as the geometric mean,arithmetic mean, arithmetic standard deviation (SD), min, median, maxand n. The geometric statistics are not presented for T_(max). Analysisof variance (ANOVA) including terms for subject and treatment are usedto calculate point estimates, and confidence intervals (CI) fortreatment differences with respect to PK parameters (90% CI) arecalculated.

The incidence of AEs was compared between treatment groups. Summarytables and individual subject listings are provided for all safetymeasurements and the results are presented by treatment group.Descriptive statistics are used to summarise data where appropriate.

Results:

The pharmacokinetic parameters measured in the single dose study(Part 1) are shown in the following table:

TABLE 2 Ratio Ratio Oral Inhalation PA-101 PA-101 PA-101 (PA-101 (30 L;(PA-101 (30 L; PK solution, aerosol, (40 L), (30 L), (30 L), 40mg))/(oral 40 mg)/(inhalation parameter 200 mg 20 mg 40 mg 40 mg 80 mgsolution (200 mg)) aerosol (20 mg)) C_(max) (ng/mL) 5.2 (±3.1) 17.8(±10.4) 88.6 (±45.5) 156 (±104) 236 (±124) x30 x8.8 T_(max) (h) 3.2(±2.1) 0.6 (±0.1) 0.6 (±0.1) 0.7 (±0.1) 0.7 (±0.1) AUC_(0-t) (h*ng/mL)29.4 (±10.4) 39.1 (±15.1)  206 (±94.3) 329 (±144) 514 (±186) x11 x8.4AUC_((0-∞)) (h*ng/mL) 33.3 (±11.7) 40.6 (±15.6)  212 (±96.0) 338 (±146)526 (±198) T_(1/2) (h) 4.3 (±1.3) 2.5 (±0.8) 2.5 (±0.7) 2.2 (±0.6) 2.1(±0.5) Bioavailability (%) 0.6 6.5 16.3 25.0 22.7 X42 X3.8 Values shownin parentheses are (±SD).

Modeling of lung deposition with an aerosol from the 30 L and 40 Ldevices using the Finaly model (Finlay, W H, and A R Martin, “Recentadvances in predictive understanding respiratory tract deposition”,Journal of Aerosol Medicine, Vol 21:189-205 (2008)) indicated that thelung deposition with the two devices should be very similar. However,the AUC value obtained with 40 mg dose using the 30 L device (338ng*hr/mL) was surprisingly high compared to the value (212 ng*hr/mL)from the 40 L device. Cromlyn sodium is not metabolized in the body andis excreted intact via bile and urine. Cromolyn sodium deposited in thelung during inhalation will appear in the plasma, and the AUC wouldtherefore be a surrogate for cromolyn sodium deposited in the lung. Anycromolyn sodium swallowed during inhalation will contribute negligiblyto the AUC since the oral bioavailability of cromolyn is only about 1%(Richards et al, J Pharmacol Exp Ther, Vol. 241, No. 3: 1028-1032(1987)). The AUC data therefore indicate that at the same dose (40 mg),the lung deposition with the 30 L device was surprisingly higher thanthat with the 40 L device.

The numbers of adverse events observed in the single dose study (Part 1)are shown in the following table:

TABLE 3 PA-101 PA-101 PA-101 Inhalation Oral (40 L), (30 L), (30 L),aerosol, solution, Adverse Event Placebo 40 mg 40 mg 80 mg 20 mg 200 mgCough 1 1 — 1 1 — Oropharyngeal pain — — — — 1 1 Rhinorrhoea 1 — — — — —Dizziness — — 2 — — — Headache — — — 1 — 1 Dysgeusia — — — — — 1Somnolence — — — 1 — — Catheter-site Reaction — — 1 — — 1 Nasopharygitis— — — — 1 — Sinusitis — — — 1 — — Abdominal Discomfort — — — — — 1Increased Appetite — 1 — — — —

Example 4: Efficacy Study

Objective

The objectives of the study are: to determine the efficacy profile ofcromolyn sodium inhalation formulation when administered using a highefficiency nebulizer in comparison with oral formulation of cromolynsodium in patients with systemic mastocytosis; to assess the safety andtolerability of cromolyn sodium inhalation formulation when administeredusing a high efficiency nebulizer; to compare the pharmacokineticprofile of cromolyn sodium inhalation formulation when administeredusing a high efficiency nebulizer in comparison with oral formulation ofcromolyn sodium in patients with indolent systemic mastocytosis.

Methodology

This is a Phase 2, randomized, double-blind, active-controlled, parallelarm, efficacy study in patients with indolent systemic mastocytosis.

At least about thirty six (36) adult human systemic mastocytosispatients are randomized to one of three treatment groups: (1) cromolynsodium inhalation formulation administered thrice daily with a highefficiency nebulizer; (2) placebo formulation administered three timesdaily with a high efficiency nebulizer; and, (3) oral formulation ofcromolyn sodium administered four times daily.

Following the Screening Visit (SV), eligible subjects enter a 4-weekWashout/Baseline Period for daily assessment of baseline symptoms usinga diary and to washout cromolyn sodium in oral cromolyn sodium users. Atthe end of the Washout Period, eligible subjects are randomized toreceive cromolyn sodium inhalation formulation using a high efficiencynebulizer or oral cromolyn sodium formulation or placebo for 6 weeks.

The main criteria for inclusion are: a) Indolent systemic mastocytosispatients uncontrolled with antihistaminic therapy; b) 18-65 years ofage; c) mastocytosis diagnosis confirmed by positive bone marrow biopsy;d) no recent systemic corticosteroid or immunosuppressive therapy; e) nohistory of cancer except basal cell carcinoma; and, f) no concurrentuncontrolled disease.

Criteria for Evaluation:

The primary efficacy variable is significant improvement in clinicalsymptoms at the end of treatment period following treatment withcromolyn sodium inhalation formulation when administered using a highefficiency nebulizer in comparison with oral formulation of cromolynsodium.

The PK parameters evaluated for plasma cromolyn sodium are maximumconcentration (C_(max)), time to maximum concentration (T_(max)),terminal elimination half-life (T_(1/2)), area under the plasmaconcentration-time curve from time=0 to time of last measurable drugconcentration (AUC_(0-t)), and area under the plasma concentration-timecurve from time=0 to infinity AUC_((0-∞)).

The safety parameters include adverse events (AEs) including assessmentof gastrointestinal disturbance (e.g., abdominal pain, nausea,vomiting), and changes in vital signs and clinical laboratory tests.

Results:

At the end of the treatment period, patients exhibit a significantimprovement in clinical symptoms with minimal AEs as compared to placeboand the oral formulation of cromolyn sodium.

What is claimed is:
 1. A method of administering a therapeuticallyeffective amount of cromolyn sodium to a patient in need thereof,comprising administering to said patient an aqueous pharmaceuticalcomposition consisting of (i) from about 2% to about 6% by weight ofcromolyn sodium and (ii) an osmolarity adjusting agent consisting of (A)between about 0.1% and about 0.5% by weight of sodium chloride,inclusive of the endpoints, and (B) optionally salts of EDTA, whereinsaid pharmaceutical composition is administered to said patient byinhalation into the lungs in the form of an aerosol exhibiting arespirable fraction (≤5 μm) as measured by USP <1601> of at least about60%.
 2. The method of claim 1, wherein the salts of EDTA comprise sodiumEDTA.
 3. The method of claim 1, wherein the pharmaceutical compositioncomprises from about 5 mg to about 80 mg of cromolyn sodium.
 4. Themethod of claim 1, wherein the pharmaceutical composition comprises fromabout 36 mg to about 44 mg of cromolyn sodium.
 5. The method of claim 1,wherein the aerosol has a respirable fraction (≤3.3 μm) as measured byUSP <1601> of at least about 30%.
 6. The method of claim 1, wherein theaerosol has a respirable fraction (≤3.3 μm) as measured by USP <1601> ofat least about 30% and a respirable fraction (≤5 μm) as measured by USP<1601> of at least about 75%.
 7. The method of claim 1, wherein thesodium chloride is at a concentration of between 0.1% to 0.2% by weight,inclusive of the endpoints.
 8. The method of claim 1, wherein thepharmaceutical composition comprises about 4% by weight of cromolynsodium.
 9. The method of claim 1, wherein the pharmaceutical compositioncomprises about 6% by weight of cromolyn sodium.
 10. A method ofadministering a therapeutically effective amount of cromolyn sodium to apatient in need thereof, comprising administering to said patient anaqueous pharmaceutical composition comprising (i) from about 2% to about6% by weight of cromolyn sodium, inclusive of endpoints, and (ii) anosmolarity adjusting agent consisting of (A) between about 0.1% andabout 0.5% by weight of sodium chloride, inclusive of the endpoints, and(B) salts of EDTA, wherein said pharmaceutical composition isadministered to said patient by inhalation into the lungs in the form ofan aerosol exhibiting a respirable fraction (≤5 μm) as measured by USP<1601> of at least about 60%.
 11. The method of claim 10, wherein thepharmaceutical composition comprises about 4% by weight of cromolynsodium.
 12. The method of claim 10, wherein the pharmaceuticalcomposition comprises about 6% by weight of cromolyn sodium.
 13. Themethod of claim 10, wherein the pharmaceutical composition comprisesfrom about 5 mg to about 80 mg of cromolyn sodium.
 14. The method ofclaim 10, wherein the pharmaceutical composition comprises from about 36mg to about 44 mg of cromolyn sodium.
 15. The method of claim 10,wherein the osmolarity adjusting agent consists of (A) between about0.1% and about 0.2% by weight of sodium chloride, inclusive of theendpoints, and (B) sodium EDTA.
 16. The method of claim 15, wherein thepharmaceutical composition comprises about 4% by weight of cromolynsodium.
 17. The method of claim 15, wherein the pharmaceuticalcomposition comprises about 6% by weight of cromolyn sodium.
 18. Themethod of claim 15, wherein the pharmaceutical composition comprisesfrom about 5 mg to about 80 mg of cromolyn sodium.
 19. The method ofclaim 15, wherein the pharmaceutical composition comprises from about 36mg to about 44 mg of cromolyn sodium.
 20. The method of claim 10,wherein the salts of EDTA comprise sodium EDTA.